Re: NMDAR 길항제 - 치매, 파킨슨약 메만틴의 효과와 부작용 논문

[문형철]

초간단 정리

치매약 도네페질(아리셉트)는 아세틸콜린의 분해를 억제하여 인지장애를 치료함.

그런데 아리셉트 복용후 폭력적 치매를 일으키는 등 부작용도 많고,

            뇌보호 효과가 없어 단기적인 인지장애 치료에는 효과가 있지만 장기적으로는 치매 악화...

여기서 소개하는 메만틴(뇌 보호제)는 nmdr 수용체를 부분적으로 차단.

   nmdr 수용체는 글루타메이트 수용체이므로 ..

1) nmda 수용체를 부분적으로 차단하는 메만틴은 글루타메이트 흥분독성을 감소시키는 효과

 2) 또한 아세틸콜린 효과를 증대시켜 인지장애 치료...

https://cafe.daum.net/panicbird/S6LP/168

알비지아 파우더 + 루테올린 .. 글루탐산 독성 제거.. 치매, 파킨슨 치료...nature 2024

https://www.youtube.com/watch?v=mKHgYkCdI4Q

Curr Alzheimer Res.  Author manuscript; available in PMC 2016 Aug 28.

N-Methyl D-Aspartate (NMDA) Receptor Antagonists and Memantine Treatment for Alzheimer’s Disease, Vascular Dementia and Parkin

Published in final edited form as:

Curr Alzheimer Res. 2012 Jul; 9(6): 746–758.

doi: 10.2174/156720512801322564

PMCID: PMC5002349

NIHMSID: NIHMS738367

PMID: 21875407

N-Methyl D-Aspartate (NMDA) Receptor Antagonists and Memantine Treatment for Alzheimer’s Disease, Vascular Dementia and Parkinson’s Disease

David Olivares,1 Varun K. Deshpande,2 Ying Shi,2 Debomoy K. Lahiri,3 Nigel H. Greig,4 Jack T. Rogers,5 and Xudong Huang2,5,*

Author information Copyright and License information PMC Disclaimer

The publisher's final edited version of this article is available at Curr Alzheimer Res

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Abstract

Memantine, a partial antagonist of N-methyl-D-aspartate receptor (NMDAR), approved for moderate to severe Alzheimer’s disease (AD) treatment within the US and Europe under brand name Namenda (Forest), Axura and Akatinol (Merz), and Ebixa and Abixa (Lundbeck), may have potential in alleviating additional neurological conditions, such as vascular dementia (VD) and Parkinson’s disease (PD). In various animal models, memantine has been reported to be a neuroprotective agent that positively impacts both neurodegenerative and vascular processes. While excessive levels of glutamate result in neurotoxicity, in part through the over-activation of NMDARs, memantine—as a partial NMDAR antagonist, blocks the NMDA glutamate receptors to normalize the glutamatergic system and ameliorate cognitive and memory deficits. The key to memantine’s therapeutic action lies in its uncompetitive binding to the NMDAR through which low affinity and rapid off-rate kinetics of memantine at the level of the NMDAR-channel preserves the physiological function of the receptor, underpinning memantine’s tolerability and low adverse event profile. As the biochemical pathways evoked by NMDAR antagonism also play a role in PD and since no other drug is sufficiently effective to substitute for the first-line treatment of L-dopa despite its side effects, memantine may be useful in PD treatment with possibly fewer side effects. In spite of the relative modest nature of its adverse effects, memantine has been shown to provide only a moderate decrease in clinical deterioration in AD and VD, and hence efforts are being undertaken in the design of new and more potent memantine-based drugs to hopefully provide greater efficacy.

메만틴은 

미국과 유럽에서 

나멘다(나멘다, Forest), 악수라와 아카티놀(악수라, Merz), 에빅사와 아빅사(에빅사, 룬드벡)라는 상품명으로 

중등도에서 중증의 알츠하이머병(AD) 치료제로 승인된 

N-methyl-D- 아스파르트산염 수용체(NMDAR)의 부분 길항제로 

혈관성 치매(VD) 및 파킨슨병(PD) 같은 추가적인 신경 질환 완화에도 

잠재력이 있는 것으로 알려져 있습니다. 

다양한 동물 모델에서 

메만틴은 신경 퇴행성 및 혈관 과정 모두에 긍정적인 영향을 미치는 

신경 보호제인 것으로 보고되었습니다. 

과도한 수준의 글루타메이트는 

부분적으로 NMDAR의 과도한 활성화를 통해 신경 독성을 유발하지만, 

부분적인 NMDAR 길항제인 메만틴은 

NMDA 글루타메이트 수용체를 차단하여 

글루타메이트 시스템을 정상화하고 

인지 및 기억력 결손을 개선합니다. 

메만틴의 치료 작용의 핵심은 

NMDAR에 대한 비경쟁적 결합에 있으며, 

이를 통해 NMDAR 채널 수준에서 

메만틴의 낮은 친화력과 빠른 오프율 역학이 수용체의 생리적 기능을 보존하여 

메만틴의 내약성과 낮은 이상반응 프로파일을 뒷받침합니다. 

NMDAR 길항 작용에 의해 유발되는 생화학적 경로는 

파킨슨병에서도 중요한 역할을 하며, 

부작용에도 불구하고 

L-도파의 1차 치료를 대체할 만큼 충분히 효과적인 약물이 없기 때문에, 

메만틴은 부작용이 적으면서 

파킨슨병 치료에 유용할 수 있습니다. 

메만틴은 

부작용이 상대적으로 크지 않음에도 불구하고 

알츠하이머병과 파킨슨병의 임상적 악화를 약간만 감소시키는 것으로 나타났으며, 

따라서 더 큰 효능을 제공하기 위해 새롭고 

더 강력한 메만틴 기반 약물을 설계하기 위한 노력이 진행되고 있습니다.

Keywords: Alzheimer’s disease, Parkinson’s disease, vascular dementia, memantine, NMDAR, amantadine

INTRODUCTION

Alzheimer’s disease (AD), a neurodegenerative disorder characterized by irreversible, progressive loss of memory followed by complete dementia, is marked by cognitive decline accompanied by impaired performance of daily activities, behavior, speech and visual-spatial perception. It is the most common type of dementia among people older than 65, accounting for about 60%-70% of cases [1], associated with heterogeneous risks including genetic, epigenetic, dietary, and lifestyle factors [2].

The most striking and early symptom of AD is a loss of short-term memory (amnesia). When AD is suspected, the diagnosis is usually confirmed with behavioral assessments and cognitive tests, often followed by a brain scan. As the disorder progresses, cognitive impairment includes difficulty in producing or comprehending spoken or written language (aphasia), difficulty of execution of movements (apraxia), loss of perception (agnosia) [3], and disorientation [4]. AD may also involve behavioral changes, such as outbursts of violence or excessive passivity in people who have no previous history of such behavior [5, 6]. Gradually, basic physiological functions are lost, ultimately leading to death.

AD afflicts at least 26 million people throughout the world [7] of which 5.4 million are Americans [8]. In the US, in 2011, it is estimated that at least $183 billion will be spent on direct AD care [8] and these costs will rise as the population ages. Several FDA-approved drugs are currently in use for the treatment of AD, however they mostly bring symptomatic relief and do not cure AD. Such an absence of treatment options sets the stage for the present review, which is primarily focused on the physiological role and utility of NMDAR antagonists, especially memantine, and its treatment not only for AD but other neurodegenerative disorders also, such as Vascular Dementia (VD) and Parkinson’s Disease (PD). The present review summarizes the recent advances in pathogenic processes underlying these diseases, including the amyloid pathway, pharmacology of NMDARs, glutamatergic transmission and the utility of NMDAR antagonists for therapy. Keeping the current interest of the field in mind, we will place a special emphasis on memantine treatment. It is worth mentioning that several aspects of memantine, such as its molecular basis [9], pharmacology [10] and clinical trials [11] have been previously discussed in this journal. However, the present review brings forward distinctly the unique role of memantine in treating AD, VD and PD in a comprehensive manner.

소개

알츠하이머병(AD)은 비가역적이고 점진적인 기억력 상실에 이어 완전한 치매로 진행되는 신경 퇴행성 질환으로, 일상 활동, 행동, 언어 및 시각-공간 지각 장애를 동반하는 인지 기능 저하가 특징입니다. 65세 이상에서 가장 흔한 치매 유형으로, 약 60~70%를 차지하며[1] 유전적, 후성유전적, 식이 및 생활습관 요인[2]을 포함한 이질적인 위험과 관련이 있습니다[2].

알츠하이머병의 가장 두드러진 초기 증상은 단기 기억 상실(기억 상실증)입니다. 알츠하이머병이 의심되면 보통 행동 평가와 인지 검사를 통해 진단을 내리며, 뇌 스캔을 통해 진단을 내리는 경우가 많습니다. 장애가 진행됨에 따라 인지 장애에는 구어 또는 문어의 산출이나 이해의 어려움(실어증), 동작 수행의 어려움(실어증), 지각 상실(실어증)[3], 방향 감각 상실[4] 등이 포함됩니다. AD는 또한 이전에 그러한 행동의 병력이 없는 사람들에게서 폭력성 폭발이나 과도한 수동성과 같은 행동 변화를 수반할 수 있습니다 [5, 6]. 점차적으로 기본적인 생리적 기능이 상실되어 궁극적으로 사망에 이르게 됩니다.

알츠하이머병은 전 세계적으로 최소 2,600만 명이 앓고 있으며[7], 이 중 540만 명이 미국인입니다[8]. 미국에서는 2011년에 최소 1,830억 달러가 알츠하이머병 치료에 직접 지출될 것으로 추정되며[8], 인구 고령화에 따라 이러한 비용은 증가할 것으로 예상됩니다. 현재 FDA 승인을 받은 몇 가지 약물이 AD 치료에 사용되고 있지만, 대부분 증상을 완화할 뿐 AD를 완치하지는 못합니다.

이러한 치료 옵션의 부재는 본 리뷰의 배경이 되며,

본 리뷰에서는 주로 NMDAR 길항제,

특히 메만틴의 생리적 역할과 유용성,

그리고 AD뿐만 아니라 혈관성 치매(VD) 및 파킨슨병(PD) 등

다른 신경 퇴행성 질환에 대한 치료에도 초점을 맞추고 있습니다.

본 리뷰에서는

아밀로이드 경로,

NMDAR의 약리학,

글루탐산 전달 및 치료를 위한 NMDAR 길항제의 유용성을 포함하여

이러한 질환의 기저에 있는 병인 과정에 대한 최근의 진전을 요약합니다.

이 분야의 현재 관심을 염두에 두고 메만틴 치료에 특별히 중점을 둘 것입니다.

메만틴의 분자적 기초[9], 약리학[10], 임상시험[11]과 같은

메만틴의 여러 측면이 본 저널에서 이전에 논의되었다는 점을 언급할 가치가 있습니다.

그러나

본 리뷰에서는

AD, VD 및 PD 치료에 있어 메만틴의 고유한 역할을

포괄적으로 제시합니다.

ALZHEIMER’S DISEASE PATHOGENESIS, NMDARS AND MEMANTINE TREATMENT

Alzheimer’s Disease Pathology and NMDARs

Cognitive impairment in AD is caused, in large part, by the death of cholinergic neurons in the basal forebrain area [12]. Therefore, well characterized in the AD brain are a deficit in acetylcholine (ACh) and classical cholinergic markers, epitomized by choline acetyltransferase and acetylcholineseterase [2, 13].

AD neuropathology is routinely characterized by the accumulation of insoluble amyloid protein that originates from the amyloidogenic processing of a much larger metalloprotein – amyloid precursor protein (APP) [14] that leads to the formation of extracellular neuritic amyloid plaques containing the peptide- beta amyloid peptide (Aβ, see Fig. 1). The other major pathological hallmarks include neurofibrillary tangles (NFTs) that are comprised of misfolded, abnormally phosphorylated microtubule-associated tau protein [15], inflammatory changes with astrocytosis and microgliosis [16], oxidative stress [17, 18] and neuropil threads that have been found in the post-mortem AD brain [19], and in addition, a variety of other neurochemical and cellular alterations that result in anatomic as well as functional impairment of the neurotransmitter systems.

알츠하이머병 병리와 NMDARs

알츠하이머병의 인지 장애는

대부분 기저 전뇌 영역의

콜린성 뉴런의 사멸로 인해 발생합니다[12].

따라서

AD 뇌에서 잘 특징지어지는 것은

아세틸콜린(ACh)과 콜린 아세틸 트랜스퍼라제 및 아세틸콜린 세터라제로 대표되는

고전적인 콜린성 마커의 결핍입니다 [2, 13].

AD 신경 병리학은

일반적으로 훨씬 더 큰 금속 단백질인 아밀로이드 전구체 단백질(APP)의

아밀로이드 생성 과정에서 발생하는

불용성 아밀로이드 단백질의 축적을 특징으로 하며[14],

이는 펩티드 베타 아밀로이드 펩티드(Aβ, 그림 1 참조)를 포함하는

세포 외 신경성 아밀로이드 플라크의 형성으로 이어집니다.

AD neuropathology is routinely characterized by the

accumulation of insoluble amyloid protein

that originates from the amyloidogenic processing of a much larger metalloprotein

– amyloid precursor protein (APP) [14]

that leads to the formation of extracellular neuritic amyloid plaques

containing the peptide- beta amyloid peptide (Aβ, see Fig. 1)

다른 주요 병리학적 특징으로는

잘못 접히고 비정상적으로 인산화 된 미세 소관 관련

타우 단백질로 구성된 신경 섬유 엉킴(NFT) [15],

성상 세포증 및 미세 아교 증을 동반 한 염증 변화 [16],

산화 스트레스 [17]

등이 있습니다, 18]

또한 사후 알츠하이머병 뇌에서 발견되는

뉴로필 실[19], 그리고 신경전달물질 시스템의 해부학적 및 기능적 손상을 초래하는

다양한 기타 신경화학 및 세포 변화 등이 있습니다.

Fig. (1)

Schematic illustration of APP protein and its Aβ product after cleavage by α-, β- and γ-secretases. β- and γ-secretase cleaves on the N- and C-terminal ends of the Aβ region respectively. γ-Secretase cleavage yields a 39–43 amino acid product. Long and more fiblillogenic 42–43 amino acid Aβ species are implicated in AD pathogenesis and may seed the formation of Aβ40 fibrils. Mutations in the APP gene and in genes encoding proteins known as presenilins increase the production of long Aβ. Presenilins-1 and −2 is thought function as γ-secretases (for a review, see [142]).

α-, β- 및 γ-세크레타제에 의해 절단된 후의 APP 단백질과 그 Aβ 생성물의 모식도.

β- 및 γ-세크레타제는 각각 Aβ 영역의 N-말단과 C-말단에서 절단됩니다. γ-세크레타제 절단은 39-43개의 아미노산 생성물을 생성합니다. 길고 더 많은 섬유소원성 42-43 아미노산 Aβ 종은 AD 발병에 관여하며 Aβ40 원 섬유의 형성에 씨앗이 될 수 있습니다. APP 유전자와 프레세닐린으로 알려진 단백질을 암호화하는 유전자의 돌연변이는 긴 Aβ의 생성을 증가시킵니다. 프레세닐린-1과 -2는 γ-세크레타제로서 기능하는 것으로 알려져 있습니다(자세한 내용은 [142] 참조).

Although genetic, biochemical and neuropathological data strongly point to Aβ and amyloid plaque formation as a central event in AD pathogenesis [20], the etiopathology of AD remains unclear. A considerable weight of data suggests that it is polygenic and multifactorial [21] and that, likely, Aβ metabolism is sensitive to a range of influences and multiple mechanisms that can cause a shift towards the pathogenic pathways that lead to AD [22]. A small fraction of patients develop AD before the age of 65 known as early onset familial AD (FAD) that is believed to be caused by ~200 mutations in one of three genes: APP (on chromosome 21), and presenilin-1 and −2 (PS1, PS2) (31, 177 and 14 mutations, respectively) [http://www.molgen.ua.ac.be/ADMutations]. A commonality of these numerous mutations is that they, albeit via different routes, increase generation of Aβ and, in particular, the ratio of Aβ42: Aβ40 [23]. Major evidence indicates that soluble aggregates of Aβ and Aβ-derived diffusible ligands (ADDLs) target synapses and impair memory and also can induce cellular dysfunction. Recently, it has been suggested that APP proteolysis generates additional fragments that contribute to neuronal dysfunction [24].

유전적, 생화학적 및 신경 병리학 데이터는

Aβ와 아밀로이드 플라크 형성이

AD 발병의 중심 사건임을 강력하게 시사하지만[20],

AD의 병인은 여전히 불분명합니다.

상당한 양의 데이터에 따르면

다원성 및 다인성[21]이며, A

β 대사는 다양한 영향과 여러 메커니즘에 민감하여

AD를 유발하는 병원성 경로로 전환될 수 있다고 합니다[22].

소수의 환자는

65세 이전에 AD가 발병하는 조기 발병 가족성 AD(FAD)로 알려져 있으며,

이는 세 가지 유전자 중 하나에서

약 200개의 돌연변이로 인해 발생하는 것으로 추정됩니다:

APP(21번 염색체), 프레세닐린-1 및 -2(PS1, PS2)(각각 31개, 177개, 14개 변이)

[http://www.molgen.ua.ac.be/ADMutations].

이러한 수많은 돌연변이의 공통점은

비록 다른 경로를 통해 발생하지만

Aβ의 생성, 특히 Aβ42: Aβ40의 비율을 증가시킨다는 것입니다 [23].

주요 증거에 따르면

Aβ 및 Aβ 유래 확산성 리간드(ADDL)의 용해성 응집체는

시냅스를 표적으로 하여 기억력을 손상시키고

세포 기능 장애를 유발할 수 있습니다.

최근에는

APP 단백질 분해가 신경세포 기능 장애에 기여하는 추가 조각을 생성한다고 제안되었습니다[24].

Aβ40 (40 amino acid residues) is the main soluble Aβ species that is found in the cerebrospinal fluid at low nanomolar concentrations [25]. Aβ42 (42 residues) is a minor Aβ species that is more fibrillogenic than Aβ40 and heavily enriched in interstitial plaque amyloid [26]. It is generally agreed that Aβ peptide neurotoxicity is dependent on its conformational state [27]. The in vitro solubility of synthetic Aβ42, in neutral aqueous solutions is lower than Aβ40, consequent to the hydophobicity of the additional carboxylterminal amino acids. Also, it has been demonstrated that soluble Aβ40 can be destabilized through seeding with Aβ42 fibrils [28]. However, the presence or overproduction of Aβ42 alone appears to be insufficient to initiate Aβ amyloid deposition. Overexpression‎ of APP and consequential Aβ overproduction in transgenic mice models rarely results in mice bearing full-blown Alzheimer’s-like neuropathology [29]. Rather, it appears more likely that additional neurochemical factors are required for Aβ amyloidosis.

Aβ40(40개의 아미노산 잔기)은 뇌척수액에서 낮은 나노몰 농도로 발견되는 주요 수용성 Aβ 종입니다[25]. Aβ42(42개 잔기)는 Aβ40보다 섬유소원성이 더 강하고 간질 플라크 아밀로이드에 많이 농축된 마이너 Aβ 종입니다[26]. 일반적으로 Aβ 펩타이드의 신경 독성은 그 형태적 상태에 따라 달라진다는 데 동의합니다[27]. 중성 수용액에서 합성 Aβ42의 시험관 내 용해도는 추가 카르복실 말단 아미노산의 소수성으로 인해 Aβ40보다 낮습니다. 또한, 수용성 Aβ40은 Aβ42 피브릴 시딩을 통해 불안정해질 수 있음이 입증되었습니다[28]. 그러나 Aβ42의 존재 또는 과잉 생산만으로는 Aβ 아밀로이드 침착을 시작하기에 불충분한 것으로 보입니다. 형질전환 마우스 모델에서 APP의 과발현과 그에 따른 Aβ 과생산은 본격적인 알츠하이머 유사 신경병리를 가진 마우스를 거의 만들지 못합니다 [29]. 오히려 Aβ 아밀로이드증에는 추가적인 신경화학적 요인이 필요할 가능성이 더 높아 보입니다.

Some of the potential disease-modifying treatments for AD include NMDAR blockade, use of P-sheet breakers, antioxidant strategies, Aβ-peptide vaccination, secretase inhibitors, APP synthesis inhibitors, cholesterol-lowering drugs, metal chelators and anti-inflammatory agents. Strategies targeting the Aβ protein directly include anti-Aβ immunization, γ- and P-secretase inhibitors, aggregation inhibitors and copper/zinc chelators. Interest in the use of metal chelator drugs stems from recent research suggesting that Aβ plaque formation relies upon the binding of metal ions [22]. Cholinergic drugs such as donepezil, rivastigmine and galantamine represent primary treatments for AD and are based on increasing available levels of ACh to surviving neurons. However, they have not been shown to prevent neuronal death [30] or disease progression [31]. Therefore, the eval‎uation of potential AD treatments that target other mechanisms is a major focus of current investigation and offers the greatest potential to enhance clinical management.

알츠하이머병에 대한 잠재적인 질병 조절 치료법으로는

NMDAR 차단,

P-시트 차단제 사용,

항산화 전략,

Aβ-펩타이드 백신 접종,

분비효소 억제제,

APP 합성 억제제,

콜레스테롤 저하제,

금속 킬레이트 및

항염증제 등이 있습니다.

Some of the potential disease-modifying treatments for AD include

NMDAR blockade,

use of P-sheet breakers,

antioxidant strategies,

Aβ-peptide vaccination,

secretase inhibitors,

APP synthesis inhibitors,

cholesterol-lowering drugs,

metal chelators and

anti-inflammatory agents. 

Aβ 단백질을 직접 표적으로 하는 전략에는

항-Aβ 면역,

γ- 및 P-세크레타제 억제제,

응집 억제제,

구리/아연 킬레이트 등이 있습니다.

금속 킬레이트 약물의 사용에 대한 관심은 Aβ 플라크 형성이 금속 이온의 결합에 의존한다는 최근 연구 결과에서 비롯되었습니다 [22].

도네페질, 리바스티그민, 갈란타민과 같은 콜린성 약물은

AD의 주요 치료제로,

생존 뉴런에 대한 ACh의 가용 수준을 높이는 것을 기반으로 합니다.

그러나 이러한 약물은

신경세포 사멸[30] 또는

질병 진행을 예방하는 것으로 밝혀지지 않았습니다[31].

따라서 다른 기전을 표적으로 하는 잠재적 AD 치료제의 평가는 현재 연구의 주요 초점이며 임상 관리를 개선할 수 있는 가장 큰 잠재력을 제공합니다.

Considerable evidence supports the role of dysregulated glutamate in the pathophysiology of neurodegenerative disorders and excitotoxicity [32]. Therefore, glutamate NMDARs have emerged as key therapeutic targets for AD.

Glutamate is the main excitant neurotransmitter in the mammalian brain, implicated in the excitatory postsynaptic transmission through several ionotropic and metabotropic glutamate receptors. There are three classes of glutamategated channels and a group of G-protein coupled glutamate receptors (which cause mobilization of Ca2+ from internal stores) [33, 34] named according to their activating synthetic agonist: the α-amino 3-hydroxy 5-methyl 4-isoxazole-propionic acid (AMPA) activated receptors, kainate activated receptors, and the N-methyl D-aspartate (NMDA) receptors, have great importance in long-term adaptive processes [35]. Among these, the ion channels coupled to classical NMDARs are generally the most permeable to Ca2+ [36], that can in turn function as a second messenger in various signaling pathways.

신경 퇴행성 장애 및 흥분성 독성의 병태 생리학에서

조절 장애 글루타메이트의 역할을 뒷받침하는 상당한 증거가 있습니다 [32].

따라서

글루타메이트 NMDAR은

AD의 주요 치료 표적으로 부상했습니다.

글루타메이트는

포유류 뇌의 주요 흥분성 신경전달물질로,

여러 이온성 및 대사성 글루타메이트 수용체를 통한

흥분성 시냅스 후 전달에 관여합니다.

활성화 합성 작용제에 따라 명명된 세 가지 종류의

글루타메이트 채널과

G 단백질 결합 글루타메이트 수용체 그룹(내부 저장고에서 Ca2+의 동원을 유발)[33, 34],

즉 α- 아미노 3- 히드록시 5- 메틸 4- 이소 사졸-프로피온산 (AMPA) 활성화 수용체,

카이네이트 활성화 수용체 및 N- 메틸 D- 아스파 테이트 (NMDA) 수용체는

장기 적응 과정에서 매우 중요합니다 [35]가 존재합니다.

이 중

고전적인 NMDAR에 결합된 이온 채널은

일반적으로 Ca2+에 가장 투과성이 높으며[36],

다양한 신호 경로에서 두 번째 메신저로 기능할 수 있습니다.

NMDA glutamate receptors are abundant and ubiquitously distributed throughout the central nervous system (CNS), playing a critical role in synaptic plasticity and the cellular processes that underlie learning and memory [37]. Long-term potentiation (LTP) is a representation of neuronal synaptic plasticity that consists of a brief induction phase that elicits a long-lasting enhancement in signal transmission between two neurons. A stimulus into a presynaptic cell releases neurotransmitters, mostly glutamate, onto the postsynaptic cell membrane. There, glutamate binds to AMPA receptors in the postsynaptic membrane and triggers the influx of positively charged Na+ ions into the postsynaptic cell, causing a short-lived depolarization called excitatory postsynaptic potential. In synapses that exhibit NMDAR-dependent LTP, sufficient depolarization plus binding of glutamate can unblock NMDARs and relieve the Mg2+ blockade of the NMDAR [38] allowing Ca2+ to flow into the cell.

NMDARs are tetrameric complexes (see Fig. 2) composed by two NR1 subunits (eight splice isoforms, see Fig. 3) that form the channel itself, and two NR2A, NR2B, NR2C or NR2D subunits (derived from four independent genes) [39]. NR2 subunits modulate the characteristics of the NR1 channel; therefore each combination shows different physiological and pharmacological properties [34]. For example, in vitro recombinant NMDARs composed by NR1 and NR2B subunits result in much more sensitivity to the non-competitive antagonist ifenprodil than the NR1/NR2A combination [40]. Recently, NR3 subunits have been found [41], although NR1/NR3A or NR1/NR3B complexes are not activated by glutamate but rather elicit an excitatory response through glycine activation that is independent of Ca2+ influx. Glycine is a mandatory co-factor with glutamate for NMDA channel opening [42] for binding sites onto NR1 and NR2 subunits, respectively, although a more potent inducer than glycine, an uncommon amino acid, D-serine, has been found [43].

NMDA 글루타메이트 수용체는

중추신경계(CNS) 전체에 풍부하고

어디에나 분포하며

시냅스 가소성과 학습 및 기억의 기초가 되는

세포 과정에 중요한 역할을 합니다[37].

장기 강화(LTP)는

두 뉴런 사이의 신호 전달이 오래 지속되도록 유도하는

짧은 유도 단계로 구성된 뉴런 시냅스 가소성의 한 표현입니다.

시냅스 전 세포에 자극을 주면

시냅스 후 세포막으로 신경전달물질(주로 글루타메이트)이 방출됩니다.

여기서

글루타메이트는

시냅스 후 막의 AMPA 수용체와 결합하여

양전하를 띤 Na+ 이온이 시냅스 후 세포로 유입되도록 유도하여

흥분성 시냅스 후 전위라는 단기간의 탈분극을 일으킵니다.

NMDAR 의존성 LTP를 나타내는 시냅스에서

충분한 탈분극과 글루타메이트의 결합은

NMDAR의 차단을 해제하고

NMDAR의 Mg2+ 차단을 완화하여 [38]

Ca2+가 세포로 유입되도록 할 수 있습니다.

NMDAR은 채널 자체를 형성하는 2개의 NR1 서브유닛(8개의 스플라이스 이소폼, 그림 3 참조)과 2개의 NR2A, NR2B, NR2C 또는 NR2D 서브유닛(4개의 독립 유전자에서 파생)으로 구성된 사면체 복합체( 그림 2 참조)입니다[39]. NR2 서브유닛은 NR1 채널의 특성을 조절하므로 각 조합은 서로 다른 생리적 및 약리학적 특성을 나타냅니다 [34]. 예를 들어, NR1 및 NR2B 서브유닛으로 구성된 시험관 내 재조합 NMDAR은 NR1/NR2A 조합보다 비경쟁 길항제 이펜프로딜에 훨씬 더 민감하게 반응합니다 [40].

최근에는 NR3 서브유닛이 발견되었지만[41],

NR1/NR3A 또는 NR1/NR3B 복합체는 글루타메이트에 의해 활성화되지 않고

Ca2+ 유입과 무관한

글리신 활성화를 통해 흥분성 반응을 유도합니다.

글리신은

각각 NR1 및 NR2 서브유닛에 결합하는 부위에 대해

NMDA 채널 개방을 위한

글루타메이트와 필수 보조 인자이지만[42],

글리신보다 더 강력한 유도자인 흔하지 않은

아미노산인 D-세린이 발견되었습니다[43].

Fig. (2)

Depiction of the tetrameric NMDAR at rest (right) and activated after depolarization and binding of agonists glycine and glutamate, suppressing the magnesium channel blockade (left), where antagonists MK-801 and memantine have their allosteric binding site.

안정 상태(오른쪽)와 탈분극 및 작용제 글리신과 글루타메이트의 결합 후 활성화되어 길항제 MK-801과 메만틴이 알로스테릭 결합 부위를 갖는 마그네슘 채널 차단을 억제하는 사면체 NMDAR(왼쪽)의 묘사.

Fig. (3)

Schematic structure of eight NR1 receptor isoforms (NR1A–H). Exons 5, 21 and 22 encode three splice cassettes named N1, C1 and C2. Carboxy-terminals variants are generated by splicing out of cassettes C1 and/or C2; and amino-terminal variant, by splicing out of N1. If C2 is excised, the first stop codon is suppressed, resulting in a new open reading frame that encodes the sequence named C2’ [143].

NMDARs have been implicated as a mediator of neuronal injury associated with many neurological disorders including ischemia, epilepsy, brain trauma, dementia, and neurodegenerative disorders, such as PD [44]. Pathological elevations of glutamate levels and possibly other disturbances that alter resting membrane potential (e.g. impaired metabolism) can cause over-stimulation of the NMDAR that can lead to cellular dysfunction and death [45]. Under normal conditions of synaptic transmission, the NMDAR channel is blocked by Mg2+ sitting within the channel and only activated for brief periods of time. However, under pathological conditions, the normal block of the ion channel by Mg2+ is removed and abnormally enhances NMDAR activity [46]. Over-activation of the receptor causes an excessive amount of Ca2+ influx into a neuron to then trigger a variety of processes that can lead to necrosis or apoptosis [47].

The latter process includes Ca2+ overload of mitochondria and the activation of caspases and Ca2+-dependent activation of neuronal nitric oxide synthase (nNOS), leading to increased nitric oxide (NO) production [48]. Mitochondrial Ca2+ overload disables the membrane electrochemical gradient and, therefore, the ATP synthesis [49]. In addition, as consequence of electron chain failure, there is an excessive reactive oxygen species (ROS) production, such as the superoxide anion (O2−) that reacts with NO producing peroxynitrite (ONOO−) that can in turn oxidize lipids, proteins and DNA [50]. Interestingly, Ca2+-triggered neurotoxicity depends on the activation of a determinate pathway, since Ca2+ influx through L-type voltage-gated channels or non-NMDA receptors was not toxic to cells, while a similar Ca2+ load via NMDRs was neurotoxic [51]. Increased activity of nNOS is also associated with excitotoxic cell death [52]. The nNOS is physically tethered to NMDAR through the postsynaptic density protein of 95 kDa (PSD-95) [53] and is activated by Ca2+ entry via calmodulin [41]. In fact, increased levels of NO have been detected in animal models of stroke and neurodegenerative diseases [54, 55]. It has been shown that in PSD-95 mutant mice, the production of NO induced by Ca2+ entry via NMDR is blocked without affecting nNOS expression‎, indicating the specificity of NMDAR in neurotoxicity [53].

Importantly, elevations in extracellular glutamate are not necessary to invoke an excitotoxic mechanism. Excitotoxicity can come into play even with normal levels of glutamate if NMDAR activity is increased, e.g. when neurons are injured and, thus, become depolarized [56]. Much evidence shows that the AD pathogenic cascade includes an excitotoxic component. Application of Aβ has been shown to promote endocytosis of NMDARs in cortical neurons [57]. However, the specific effects of Aβ on excitotoxicity are not yet fully understood, and the exact role of NMDAR activation in AD remains unclear, although several studies have evidenced that Aβ could bind to NMDAR and increase Ca2+ influx into the cell [58].

Many potential neuroprotective agents block virtually all NMDAR activity and therefore, have unacceptable adverse effects, such as psychosis, nausea, vomiting, and a state called dissociative anesthesia, marked by catalepsy, amnesia, and analgesia. Neuronal cell death may accompany complete NMDAR blockade that may occur with high binding affinity of some drugs towards NMDARs [59]. Such possibilities dramatize the crucial role of the NMDAR in normal neuronal processes and explain why many NMDAR antagonists have disappointingly failed to advance in clinical trials for a number of neurodegenerative diseases. To be clinically acceptable, an anti-excitotoxic therapy must block excessive activation of the NMDAR while leaving normal function relatively intact to also avoid side effects. Drugs that simply compete with glutamate for the agonist binding site and block normal physiological functions do not meet this requirement. Both competitive glutamate and glycine antagonists, even although effective in preventing glutamate -mediated neurotoxicity, cause generalized inhibition of NMDAR activities [60].

Non-competitive antagonists, like MK-801, is an effective suppressor of excitotoxicity that acts allosterically (i.e. its binding site is other than the agonist’s) in the ion channel, but due to its high affinity, slow off-rate kinetics and a lesser voltage-dependent activity, blocks the channel for a clinically unacceptable period of time [60]. Such drugs have thus failed in clinical trials to date because of the development of adverse events occurring when the drugs are administered in their therapeutic range [59].

One mechanistic type of drug that can preferentially block higher, pathological levels of glutamate is an ‘uncompetitive’ antagonist that differs from non-competitive antagonists in that it requires receptor activation by an agonist before it can bind to a separate allosteric binding site. This uncompetitive mechanism of action, unlike competitive or non-competitive antagonists, yields a drug that blocks NMDAR channels preferentially when it is excessively open and prevents an excessive flux of calcium inside the cell [61]. Most importantly, it does not substantially accumulate in the channel to interfere with normal synaptic transmission [60]. Evidence suggests that memantine acts by such a mechanism, given that it is a low, moderate affinity, uncompetitive NMDAR antagonist.

NMDAR은

허혈, 간질, 뇌 외상, 치매, 파킨슨병과 같은

신경 퇴행성 장애를 포함한 많은 신경 장애와 관련된

신경 세포 손상의 매개체로 알려져 있습니다[44].

글루타메이트 수치의 병리학적인 상승과

휴식기 막 전위를 변화시키는 기타 장애(예: 신진대사 장애)는

세포 기능 장애 및 사망으로 이어질 수 있는

NMDAR의 과자극을 유발할 수 있습니다[45].

정상적인 시냅스 전달 조건에서

NMDAR 채널은 채널 내에 존재하는

마그네슘2+에 의해 차단되고

짧은 시간 동안만 활성화됩니다.

그러나

병리학적인 조건에서는

Mg2+에 의한 이온 채널의 정상적인 차단이 제거되고

비정상적으로 NMDAR 활성이 강화됩니다 [46].

수용체가 과도하게 활성화되면

뉴런에 과도한 양의 Ca2+가 유입되어

괴사 또는 세포 사멸로 이어질 수 있는 다양한 과정이 촉발됩니다 [47].

후자의 과정에는

미토콘드리아의 Ca2+ 과부하와

카스파제의 활성화 및

Ca2+에 의존하는 신경 산화질소 합성효소(nNOS)의 활성화가 포함되어

산화질소(NO) 생성을 증가시킵니다 [48].

미토콘드리아 Ca2+ 과부하는

막 전기 화학적 구배를 무력화하여

ATP 합성을 방해합니다 [49].

또한 전자 사슬 장애의 결과로 지질, 단백질 및 DNA를 산화시킬 수 있는 NO와 반응하여 과산화물 음이온(O2-)과 같은 활성 산소 종(ROS)이 과도하게 생성되어 과산화 아질산염(ONOO-)을 생성합니다[50].

흥미롭게도

Ca2+ 유발 신경 독성은

결정적인 경로의 활성화에 의존하는데,

L형 전압 게이트 채널 또는 비-NMDA 수용체를 통한

Ca2+ 유입은 세포에 독성이 없었지만

NMDR을 통한 유사한 Ca2+ 부하는 신경 독성이 있었기 때문입니다 [51].

nNOS의 활성 증가는

흥분성 세포 사멸과도 관련이 있습니다 [52].

nNOS는

시냅스 후 밀도 단백질 95kDa(PSD-95)[53]를 통해 NMDAR에 물리적으로 묶여 있으며

칼모둘린을 통한 Ca2+ 유입에 의해 활성화됩니다[41].

실제로 뇌졸중 및 신경 퇴행성 질환의 동물 모델에서 NO 수치의 증가가 발견되었습니다 [54, 55]. PSD-95 돌연변이 마우스에서 NMDR을 통한 Ca2+ 유입으로 유도된 NO의 생성은 nNOS 발현에 영향을 주지 않고 차단되는 것으로 나타나 신경독성에서 NMDAR의 특이성을 나타냅니다 [53].

중요한 것은

흥분 독성 메커니즘을 유발하기 위해

세포 외 글루타메이트의 상승이 필요하지 않다는 점입니다.

예를 들어 뉴런이 손상되어 탈분극 상태가 되는 등 NMDAR 활성이 증가하면 글루타메이트 수치가 정상인 경우에도 흥분 독성이 작용할 수 있습니다 [56].

많은 증거에 따르면

AD 병원성 캐스케이드에는

흥분 독성 성분이 포함되어 있습니다.

Aβ의 적용은 피질 뉴런에서 NMDAR의 세포 내 증식을 촉진하는 것으로 나타났습니다 [57]. 그러나 흥분 독성에 대한 Aβ의 구체적인 효과는 아직 완전히 이해되지 않았으며, 여러 연구에서 Aβ가 NMDAR에 결합하여 세포 내 Ca2+ 유입을 증가시킬 수 있다는 사실이 입증되었지만 AD에서 NMDAR 활성화의 정확한 역할은 아직 불분명합니다 [58].

많은 잠재적 신경 보호제는

사실상 모든 NMDAR 활동을 차단하므로

정신병, 메스꺼움, 구토, 해리성 마취 상태(착란, 기억상실, 진통)와 같은

용납할 수 없는 부작용을 일으킬 수 있습니다.

신경세포 사멸은

일부 약물의 NMDAR에 대한 높은 결합 친화력으로 인해 발생할 수 있는

완전한 NMDAR 차단을 동반할 수 있습니다[59].

이러한 가능성은

정상적인 신경세포 과정에서 NMDAR의 중요한 역할을 극적으로 보여주며,

많은 NMDAR 길항제가

여러 신경 퇴행성 질환에 대한 임상시험에서

실망스럽게도 실패한 이유를 설명합니다.

임상적으로 수용 가능한 항 흥분성 치료제는

부작용을 피하기 위해

정상 기능을 비교적 그대로 유지하면서

NMDAR의 과도한 활성화를 차단해야 합니다.

단순히 작용제 결합 부위를 놓고

글루타메이트와 경쟁하여

정상적인 생리 기능을 차단하는 약물은

이 요건을 충족하지 못합니다.

경쟁적인 글루타메이트 및 글리신 길항제는

글루타메이트 매개 신경독성을 예방하는 데 효과적이지만,

NMDAR 활동을 전반적으로 억제합니다[60].

MK-801과 같은 비경쟁적 길항제는 이온 채널에서 동조적으로 작용하는(즉, 결합 부위가 작용제와 다른) 흥분 독성을 효과적으로 억제하지만 친화력이 높고, 오프율 동역학이 느리며, 전압 의존성이 낮기 때문에 임상적으로 허용할 수 없는 기간 동안 채널을 차단합니다[60]. 따라서 이러한 약물은 치료 범위 내에서 약물을 투여할 때 발생하는 부작용으로 인해 현재까지 임상 시험에서 실패했습니다 [59].

더 높은 수준의 병리학적 글루타메이트를

우선적으로 차단할 수 있는 한 가지 메커니즘적 유형의 약물은

'비경쟁적' 길항제로,

별도의 알로스테릭 결합 부위에 결합하기 전에

작용제에 의한 수용체 활성화가 필요하다는 점에서

비경쟁적 길항제와는 다릅니다.

이러한 비경쟁적 작용 메커니즘은

경쟁적 또는 비경쟁적 길항제와 달리

NMDAR 채널이 과도하게 열려 있을 때 우

선적으로 차단하여 세포 내 칼슘의 과도한 유입을 막는 약물을 생성합니다[61].

가장 중요한 것은 채널에 실질적으로 축적되어

정상적인 시냅스 전달을 방해하지 않는다는 점입니다 [60].

메만틴은

친화력이 낮고 중간 정도이며

비경쟁적인 NMDAR 길항제라는 점에서

이러한 메커니즘에 의해 작용한다는 증거가 있습니다.

MEMANTINE TREATMENT FOR ALZHEIMER’S DISEASE

Memantine (1-amino-3,5-dimethyladamantane), an amino-alkyl cyclohexane derivative was first synthesized by Eli Lilly and Company (Indianapolis, IN) and patented in 1968, as documented in the Merck Index, as a derivative of adamantine, an anti-influenza agent. It possesses a three-ring (adamantane) structure with a bridgehead amine (−NH2) that, under physiological conditions, carries a positive charge that binds at or near the Mg2+ site within the NMDAR-associated channel.

Memantine was relatively ineffective at blocking the low levels of receptor activity associated with normal neurological function but becomes increasingly effective at higher concentrations of glutamate associated with over-activation of NMDARs [60]. During normal synaptic activity, NMDA channels are open on average for only several milliseconds, and memantine is unable to act or accumulate within the channels; accordingly, synaptic activity continues largely unabated [56]. During prolonged activation of the receptor, however, as occurs under excitotoxic conditions, memantine becomes a highly effective blocker. In addition to its low to moderate affinity, memantine blocks/unblocks the NMDAR ion channel with rapid kinetics and high voltage dependency [62].

These properties are thought to underlie the apparent ability of memantine to allow normal physiological function of the receptor while impairing pathological activation. Blocking NMDARs has also been reported to mitigate Aβ-induced degeneration of cholinergic neurons in the rat magnocellular nuclear basalis and in rat hippocampal neurons [63–65]. Preclinical data suggest that NMDAR-mediated excitotoxicity may be linked to the effects of abnormal Aβ deposition in AD. More recently, memantine has been found to lower levels of secreted APP and Aβ peptide levels in neuronal cultures and in APP-Swe+PS1 AD transgenic mice [66, 67]. This is important as Aβ accumulation is the precipitating event in AD that leads to synaptic loss among other pathological features. Aβ is known to alter neuronal structure by mechanisms that involve the NMDARand inhibition of the NMDAR can reduce the toxic effects of Aβ.

As a currently approved drug, memantine is indicated for the symptomatic treatment of moderate to severe AD, and has been associated with a moderate decrease in clinical deterioration in AD [68]. Its usefulness has been proved in several clinical trials in which it has shown little but statistically significant improvements [69–72], also assessed by brain imaging [73]. Several systematic reviews of randomized controlled trials have established that memantine has small but helpful actions on cognition, mood, behavior, and the ability to perform daily activities in moderate to severe AD [74–76] nevertheless, the action of the drug in mild to moderate AD remains largely unknown. Importantly, memantine appears capable of achieving its pharmacological actions in a clinically well-tolerated manner and does not show the adverse effects typically associated with high-affinity NMDA-blockers. In trials reporting adverse effects, the primary memantine-induced adverse actions found were infrequent and comparable to placebo such as dizziness, occasional restlessness/agitation, constipation, ocular effects (cataracts, conjunctivitis), nausea, dyspnea, confusion, headache, fatigue, rash, diarrhea and urinary incontinence [77, 78]. On the basis of successful clinical trials, the use of memantine in the modulation of glutamatergic function may therefore represent a useful strategy for the treatment of AD. Furthermore, in vitro and clinical data indicate no adverse interactions between the approved cholinesterase inhibitors and memantine [79, 80].

Because memantine has exhibited efficacy and safety in placebo-controlled trials in patients with moderate to severe AD, the combination of memantine and various cholinesterase inhibitors appears well tolerated and they seem act synergistically due to their distinct mechanisms of action [81–85].

At present, a series of second generation memantine derivatives are currently in development and may have even greater neuroprotective properties than memantine [9, 86]. Whether and how these drugs translate to clinical medicine are awaited with interest.

알츠하이머병에 대한 메만틴 치료제

아미노-알킬 시클로헥산 유도체인 메만틴(1-아미노-3,5-디메틸아다만탄)은

항인플루엔자 치료제인 아다만틴의 유도체로

1968년 Eli Lilly and Company(인디애나폴리스, 인디애나)에서 처음 합성되어

머크 인덱스에 기록된 대로 특허를 획득한 물질입니다.

아다만틴은 생리학적 조건에서 NMDAR 관련 채널 내의 마그네슘2+ 부위 또는 그 근처에 결합하는 양전하를 띠는 교두보 아민(-NH2)이 있는 3고리(아다만틴) 구조를 가지고 있습니다.

메만틴은

정상적인 신경 기능과 관련된 낮은 수준의 수용체 활동을 차단하는 데는

상대적으로 효과적이지 않지만,

NMDAR의 과활성화와 관련된 높은 농도의 글루타메이트에서는 점점 더 효과적입니다 [60].

정상적인 시냅스 활동 중에는

NMDA 채널이 평균 수 밀리초 동안만 열려 있고

메만틴은 채널 내에서 작용하거나 축적할 수 없으므로

시냅스 활동은 거의 감소하지 않고 계속됩니다 [56].

그러나

흥분성 조건에서와 같이 수용체가 장기간 활성화되는 동안 메만틴은

매우 효과적인 차단제가 됩니다.

메만틴은

낮거나 중간 정도의 친화력 외에도 빠른 동역학 및 높은 전압 의존성으로

NMDAR 이온 채널을 차단/차단 해제합니다 [62].

이러한 특성은

메만틴이 수용체의 정상적인 생리적 기능을 허용하는 동시에

병리적 활성화를 손상시키는 명백한 능력의 기초가 되는 것으로 생각됩니다.

NMDAR을 차단하면

쥐의 자상세포핵 기저핵과 쥐 해마 신경세포에서

콜린성 신경세포의 Aβ 유발 변성을 완화하는 것으로 보고되었습니다 [63-65].

전임상 데이터에 따르면

NMDAR 매개 흥분 독성은

알츠하이머병에서 비정상적인 Aβ 침착의 영향과 관련이 있을 수 있다고 합니다.

최근에는 메만틴이 신경세포 배양과 APP-Swe+PS1 AD 형질전환 마우스에서 분비되는 APP 및 Aβ 펩타이드 수치를 낮추는 것으로 밝혀졌습니다 [66, 67]. 이는 Aβ 축적이 다른 병리학적 특징 중에서도 시냅스 손실을 유발하는 AD의 촉발 사건이기 때문에 중요합니다. Aβ는 NMDAR과 관련된 메커니즘에 의해 신경세포 구조를 변화시키는 것으로 알려져 있으며, NMDAR을 억제하면 Aβ의 독성 효과를 줄일 수 있습니다.

현재 승인된 약물인 메만틴은

중등도에서 중증의 알츠하이머병의 증상 치료에 사용되며,

알츠하이머병의 임상적 악화를 어느 정도 감소시키는 것과 관련이 있습니다 [68].

메만틴의 유용성은

뇌 영상으로 평가한 여러 임상 시험에서 미미하지만

통계적으로 유의미한 개선 효과를 보였으며[69-72],

뇌 영상으로도 그 유용성이 입증되었습니다[73].

무작위 대조 시험에 대한 여러 체계적인 검토를 통해 메

만틴이 중등도에서 중증의 알츠하이머병 환자의

인지, 기분, 행동 및 일상 활동 수행 능력에

작지만 도움이 된다는 사실이 밝혀졌지만[74-76],

경증에서 중등도의 알츠하이머병에서 메만틴의 작용은

아직 많이 알려지지 않은 상태입니다.

중요한 것은

메만틴이 임상적으로 내약성이 좋은 방식으로 약리 작용을 할 수 있고

일반적으로 고친화성 NMDA 차단제와 관련된 부작용이 나타나지 않는다는 점입니다.

부작용을 보고한 임상시험에서

메만틴으로 인한 주요 부작용은

어지러움,

때때로 불안/초조, 변비, 안구 영향(백내장, 결막염),

구역, 호흡곤란, 혼란, 두통,

피로, 발진, 설사, 요실금 등

드물고 위약과 비슷한 수준이었습니다 [77, 78].

따라서

성공적인 임상 시험에 근거하여

글루탐산 기능 조절에 메만틴을 사용하는 것은

알츠하이머 치료에 유용한 전략이 될 수 있습니다.

또한, 시험관 및 임상 데이터에 따르면 승인된

콜린 에스 테라 제 억제제와 메

만틴 사이에 부정적인 상호 작용이 없음을 나타냅니다 [79, 80].

메만틴은

중등도에서 중증 AD 환자를 대상으로 한 위약 대조 시험에서 효능과 안전성을 입증했기 때문에

메만틴과 다양한 콜린 에스 테라 제 억제제의 조합은

내약성이 우수하고 서로 다른 작용 메커니즘으로 인해 상승적으로 작용하는 것으로 보입니다 [81-85].

현재 일련의 2세대 메만틴 유도체가 개발 중이며

메만틴보다 훨씬 더 뛰어난 신경 보호 특성을 가질 수 있습니다 [9, 86].

이러한 약물이 임상에 적용될 수 있을지 여부와 그 방법에 관심이 모아지고 있습니다.

Go to:

MEMANTINE TREATMENT FOR VASCULAR DEMENTIA

Memantine has also been described as effective and well tolerated for the treatment of mild to moderate VD in several randomized clinical trials [87–89]. VD ranks second in preval‎ence as a form of dementia after AD [1], and they often co-exist. It is not infrequent that confusion can occur between both disorders, due to the similarity of their clinical symptoms. VD is a degenerative cerebrovascular disease that leads to a progressive decline in memory and cognitive functioning. The root of this issue relates to a chronic reduced cerebral blood flow (vascular insufficiency) carrying oxygen and nutrients to the brain that may be impaired by a strategic infarct (ischemia) or small (silent) multi-infarcts, hemorrhagic cerebrovascular disease, or can derive from small vessel disease (including lacunar lesions and Binswanger’s disease) [90]. Apart from acute ischemia from embolic or atherothrombotic large vessels occlusion, ischemic-hypoxic brain lesions also can be originated by cardiovascular diseases, such as hypertension or diabetes, which cause a narrowing of the lumen of small vessels [91]. In addition, senile arteriolosclerosis produces tortuosity and elongation of arterioles [92].

Since it may be partly preventable, VD needs to be differentiated from other causes of dementia such as AD, Lewy body-type dementia and PD. Special attention has to be given when attempting to make a differential diagnosis, to the following steps that may lead to a diagnosis of VD [93]:

혈관성 치매에 대한 메만틴 치료

메만틴은

여러 무작위 임상 시험에서 경증에서 중등도의

혈관성 치매 치료에 효과적이고 내약성이 좋은 것으로 나타났습니다 [87-89].

혈관성 치매는

알츠하이머병 다음으로 유병률이 높은 치매의 한 형태이며[1],

종종 공존하는 경우가 많습니다.

임상 증상이 유사하기 때문에 두 질환을 혼동하는 경우가 드물지 않습니다.

VD는 기억력과 인지 기능이 점진적으로 저하되는 퇴행성 뇌혈관 질환입니다. 이 문제의 근원은 뇌에 산소와 영양분을 운반하는 만성적인 뇌 혈류 감소(혈관 기능 부전)와 관련이 있으며, 이는 전략적 경색(허혈) 또는 작은(조용한) 다발성 경색, 출혈성 뇌혈관 질환에 의해 손상되거나 소혈관 질환(열공 병변 및 빈스방거병 포함)에서 파생될 수 있습니다[90]. 색전성 또는 죽상 혈전성 대혈관 폐색으로 인한 급성 허혈 외에도 허혈성 저산소성 뇌 병변은 고혈압이나 당뇨병과 같은 심혈관 질환으로 인해 작은 혈관의 내강이 좁아지는 경우에도 발생할 수 있습니다 [91]. 또한 노인성 동맥경화증은 세동맥의 비틀림과 신장을 일으킵니다 [92].
부분적으로 예방할 수 있기 때문에 VD는 알츠하이머병, 루이체형 치매 및 PD와 같은 다른 치매의 원인과 구별해야 합니다. 감별 진단을 시도할 때는 VD 진단으로 이어질 수 있는 다음 단계에 특별한 주의를 기울여야 합니다[93]:

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Oxygen and glucose deprivation are followed by an elevation of extracellular glutamate both in ischemic brain damage and traumatic brain injury [50] that results in consequent NMDR overactivation and massive Ca2+ influx. Failure of astrocyte functions also has been reported [94] such as maintenance of blood-brain barrier (BBB) cells in cerebral microvasculature and endothelial permeability [95]. Disruption of tight junctions among endothelial cells, degradation of the basal lamina and extracellular matrix by metalloproteinases-2 and −9 are involved in BBB breakdown and cerebral hemorrhagia [96–98]. In addition, adhesion and transmigration of leukocyte occurs, leading to activation of an inflammatory response [99]. For a review of downstream processes after calcium entry in ischemia, see Ref. [48].

In general, cerebral lesions after ischemic injury begin with an initial reversible stage where neurons finally become necrotic [100]. The cells of the ischemic core undergo anoxic depolarizations that expand to the penumbral region and a lack of energy that leads to necrosis [101]. Since the ischemic area grows as the number of peri-infarct depolarizations increases, the extension of severe damaged area can be attenuated by blocking NMDAR-mediated depolarizations [102].

산소와 포도당이 부족하면

허혈성 뇌 손상과 외상성 뇌 손상 모두에서

세포 외 글루타메이트가 상승하여 [50]

결과적으로 NMDR이 과활성화되고 Ca2+가 대량으로 유입됩니다.

성상교세포 기능의 장애도 보고되었습니다[94](예: 뇌 미세혈관에서 혈액뇌장벽(BBB) 세포의 유지 및 내피 투과성[95]). 내피 세포 간의 긴밀한 접합의 파괴, 메탈로프로테아제-2 및 -9에 의한 기저층 및 세포 외 기질의 분해는 BBB 분해 및 뇌출혈에 관여합니다 [96-98]. 또한 백혈구의 접착과 이동이 발생하여 염증 반응이 활성화됩니다 [99]. 허혈에서 칼슘 진입 후 다운 스트림 프로세스에 대한 검토는 참조를 참조하십시오. [48].

일반적으로 허혈성 손상 후 뇌 병변은 뉴런이 최종적으로 괴사되는 초기 가역적 단계로 시작됩니다 [100]. 허혈성 코어의 세포는 무산소 탈분극을 겪으며, 이는 반뇌 영역으로 확장되고 에너지 부족으로 인해 괴사로 이어집니다 [101].

허혈 영역은

경색 주변 탈분극의 수가 증가함에 따라 증가하기 때문에

NMDAR 매개 탈분극을 차단함으로써

심각한 손상 영역의 확장을 약화시킬 수 있습니다 [102].

Go to:

PARKINSON’S DISEASE PATHOGENESIS, NMDARS, GLUTAMATERGIC TRANSMISSION AND MEMANTINE TREATMENT

Parkinson’s Disease Pathology, NMDARs and Glutamatergic Transmission

PD is the second most frequent progressive-type neurodegenerative disorder after AD [103] and represents, like AD, a large health burden to society. Approximately 1% of the population over 60 years of age is affected [104]. Classical clinical symptoms include tremors; bradykinesia, or slowness of movement; and rigidity, or akinesia.

The primary underlying pathology of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) that innervates the striatum. At post-mortem examination, the depletion frequently exceeds 90% [105] with consequent loss of neuronal systems responsible for motor functions. Besides, cell death is not limited to dopaminergic neurons in SNpc and can expand to other areas of the brain, leading to extensive neuronal death. It is not infrequent to find dementia in patients afflicted by PD. A further archetypal hallmark is the formation of intracytoplasmic inclusions, termed Lewy bodies, in remaining neurons [106].

To date, no curative treatment for PD exists but symptomic control can be achieved. The most effective treatments are based on the replacement of dopamine (DA) loss using either the precursor of DA, L-dihydroxyphenylalanine (L-dopa), or agonist-mediated stimulators of DA receptors, epitomized by pramipexole or ropinirole. Essentially, all patients require L-dopa at some stage of disease progression, in spite of its adverse effects, such as the “wearing-off” phenomenon – relating to the shortening of sustainable pharmacological activity [107] as occurs when the symptoms of PD, attenuated by the treatment, become more intense prior to the next expected dose. Albeit that L-dopa is associated with dyskinesia or diminished voluntary movements and the presence of involuntary movements, it must be recognized that, since L-dopa’s clinical introduction, survival with PD has been considerably prolonged [108].

NMDARs are very abundant in the striatum [109], comprised by putamen and caudate nucleus, where they regulate the release of neurotransmitters like γ-aminobutyric acid (GABA) and ACh [110]. NMDARs downstream of the striatum also participate in modulating the activities of basal ganglia circuit and are present in the subthalamic nucleus (STN), globus pallidus internus (GPi) [111], and cerebral cortex [112]. The activity of NMDARs is largely regulated by dopaminergic afferents. D1 receptor agonists elicit a fast enhancement of NMDA-induced depolarization of striatal cells, whereas D2 receptor agonists attenuate this [113].

Execution of voluntary movement starts with the cortex (executive) signaling the caudate and putamen via glutamatergic projections or from the SNpc via dopamine. The Striatum then sends inhibitory GABAergic signals to GPi leads to disinhibition of the thalamic ventral anterior (VA). This leads to stimulatory signaling of the motor cortex by the thalamic VA and initiation of movement. As described, PD is characterized by depletion of dopaminergic neurons, leading to a disinhibition of striatal neurons that have inhibitory D2 dopaminergic receptors and project to the globus pallidus externus (GPe), and to a decrease of striatal neuron activity projecting to the GPi and the substantia nigra pars reticulata (SNpr) that have D1 excitatory dopaminergic receptors [114]. All these striatal efferent pathways are mediated by GABA and are inhibitory so that GPe projection to the STN (also inhibitory) is reduced. Therefore, the suppression of dopaminergic modulation disinhibits STN neurons, rendering them overactive [115]. The enhanced activity of excitatory glutamatergic STN projections to GPi and SNpr (besides lack of inhibitory input from the GPe stated above) further enhance the activity of their GABAergic neurons [116]. Spontaneous movement is reduced by inhibiting the activity of thalamic glutamatergic and excitatory VA projections VA to the motor frontal cortex (see Fig. 4A and B). Acetylcholinergic neurons in the brainstem and basal forebrain areas, are regulated by prefrontal cortex glutamatergic projections, and seem to be of special relevance in modulating motor, emotional and mnemonic functions [117], therefore a decrease of thalamocortical input entails a deficit of ACh, leading to a decline in voluntary movements. Likewise, the striatum and SNpc can receive glutamatergic excitatory input from the neocortex [118].

파킨슨병 병인, NMDAR, 글루탐산 전달 및 메만틴 치료

파킨슨병 병리, NMDAR 및 글루탐산염 전달

파킨슨병은

알츠하이머병에 이어 두 번째로 흔한 진행성 신경 퇴행성 질환이며[103],

알츠하이머병과 마찬가지로 사회에 큰 보건 부담을 초래합니다.

60세 이상 인구의 약 1%가 이 질환의 영향을 받습니다[104].

전형적인 임상 증상으로는 떨림, 서동증 또는 움직임의 느림, 경직 또는 운동 이상증 등이 있습니다.

PD의 주요 근본 병리는

선조체를 자극하는 흑질 흑질(SNpc)의 도파민성 뉴런이 소실되는 것입니다.

사후 검사에서

도파민 신경세포의 고갈은 종종 90%를 초과하며[105],

결과적으로 운동 기능을 담당하는 신경계가 소실됩니다.

게다가 세포 사멸은 SNpc의 도파민 신경세포에만 국한되지 않고 뇌의 다른 영역으로 확대되어 광범위한 신경세포 사멸로 이어질 수 있습니다. 파킨슨병 환자에게서 치매가 발견되는 것은 드문 일이 아닙니다. 또 다른 전형적인 특징은 남은 뉴런에 루이체라고 하는 세포질 내 내포물이 형성된다는 것입니다 [106].

현재까지

파킨슨병에 대한 완치 치료법은 없지만

증상을 조절할 수는 있습니다.

가장 효과적인 치료법은

DA의 전구체인 L-디하이드록시페닐알라닌(L-dopa) 또는

프라미펙솔 또는 로피니롤로 대표되는 DA 수용체의 작용제 매개 자극제를 사용하여

도파민(DA) 손실을 대체하는 것입니다.

기본적으로 모든 환자는 질병 진행의 어느 단계에서 L-도파가 필요하지만, 치료로 약화된 PD 증상이 다음 예상 용량 이전에 더 심해질 때 발생하는 지속 가능한 약리 활성의 단축과 관련된 “마모” 현상[107]과 같은 부작용에도 불구하고 L-도파가 필요합니다. L- 도파가 운동 이상증 또는 자발적 운동 감소 및 불수의적 운동의 존재와 관련이 있지만, L- 도파의 임상 도입 이후 PD 생존 기간이 상당히 연장되었다는 사실을 인식해야합니다 [108].

NMDAR은

푸타멘과 꼬리핵으로 구성된 선조체[109]에 매우 풍부하며,

γ- 아미노낙산(GABA) 및 ACh [110]와 같은

신경전달물질의 방출을 조절합니다[109].

선조체의 하류에 있는 NMDAR은 기저핵 회로의 활동을 조절하는 데도 관여하며 시상하핵(STN), 시상내핵(GPi)[111], 대뇌 피질[112]에도 존재합니다. NMDAR의 활동은 주로 도파민성 구심체에 의해 조절됩니다. D1 수용체 작용제는 NMDA에 의한 선조체 세포의 탈분극을 빠르게 강화하는 반면, D2 수용체 작용제는 이를 약화시킵니다 [113].

자발적 운동의 실행은 피질(집행)이 글루타메이트 투영을 통해 또는 도파민을 통해 SNpc에서 꼬리핵과 푸타멘에 신호를 보내는 것으로 시작됩니다. 그런 다음 선조체는 억제성 GABAergic 신호를 GPi로 보내 시상 복부 전방(VA)의 억제를 유도합니다. 이는 시상 VA에 의한 운동 피질의 자극 신호와 운동의 시작으로 이어집니다. 설명한 바와 같이, PD는 도파민성 뉴런의 고갈을 특징으로 하며, 억제성 D2 도파민성 수용체를 가지고 있고 외측 구상체(GPe)로 돌출하는 선조체 뉴런의 억제와 D1 흥분성 도파민성 수용체를 가지고 있는 GPi 및 흑질 흑질(SNpr)으로 돌출하는 선조체 뉴런 활동의 감소로 이어집니다 [114]. 이러한 모든 선조체 원심성 경로는 GABA에 의해 매개되며 억제성이어서 STN으로의 GPe 투사(역시 억제성)가 감소합니다. 따라서 도파민 조절을 억제하면 STN 뉴런이 억제되어 뉴런이 과잉 활동하게 됩니다[115]. 위에서 언급한 GPe의 억제 입력 부족 외에도 GPi 및 SNpr에 대한 흥분성 글루탐산성 STN 투영의 활동이 강화되면 GABAergic 뉴런의 활동이 더욱 강화됩니다 [116]. 운동 전두엽 피질에 대한 시상 글루탐산 및 흥분성 VA 투사 VA의 활동을 억제함으로써 자발적인 움직임이 감소합니다( 그림 4A 및 B 참조). 뇌간 및 기저 전뇌 영역의 아세틸콜린성 뉴런은 전전두피질 글루타메이트 투영에 의해 조절되며 운동, 정서 및 니모닉 기능 조절에 특별한 관련이 있는 것으로 보입니다[117], 따라서 시상 피질 입력의 감소는 ACh의 결핍을 수반하여 자발적 움직임의 감소로 이어집니다. 마찬가지로 선조체와 SNpc는 신피질로부터 글루타메이트 흥분성 입력을 받을 수 있습니다 [118].

Fig. (4)

Classical model of normal activity of the basal ganglia and malfunctioning in PD (reviewed in Ref. [114]). Thin arrows indicate downregulation and thick arrows upregulation. Blue arrows show glutamatergic activatory efferents, red arrows indicate inhibitory GABAergic efferents and green arrows, activatory/inhibitory projections. 

(A) The ‘direct pathway’ is comprised of striatal neurons with D1 activatory dopaminergic receptors and their GABAergic efferent projections to the globus pallidus internus (GPi) which together the SNpr transmit inhibitory signals via GABAergic output to the thalamic ventral anterior (VA) nucleus. The ‘indirect pathway’ is comprised of striatal neurons with D2 inhibitory dopaminergic receptors. The striatum (composed of caudate and putamen) projects GABAergic output to the globus pallidus externus (GPe). From this point, they synapse to the nucleus subthalamicus (STN), from which glutamatergic activatory projections reach the GPi and the substantia nigra (SNpc/SNpr). The subthalamic nucleus also gets excitatory input directly from the cortex and induces the GPi to increase GABA release in the VA. While GPe keeps it in check, the SNpc dopamine binds D2 receptors to inhibit this pathway, blocking the inhibition of the subthalamic circuit by GPe. Additionally, the striatum and the SNpc receive glutamatergic efferents from the neocortex.

(B) Loss of dopaminergic afferents (broken green arrows) entails a dis-repression of striatal D2 neurons leads to over-activity of their GABAergic projections to the GPe, and this in turn decreases its GABAergic efferent activity to the STN. As a consequence, STN glutamatergic projections to the GPi render over-active, increasing GABAergic output from the GPi to the VA. On the contrary, the D1 striatal neurons are underactive, therefore the GABAergic output to the GPi and to the SNpr are reduced and consequently the GABAergic output from both to the VA is increased. As a consequence in both cases, the loss of dopaminergic projections causes a failure to desinhibit the thalamocortical output, leading to bradykinesia, a typical symptom in PD. 

(C) (D) Possible targets at the basal ganglia level of NMDAR antagonists amantadine and memantine. Broken arrows mean suppression of output projections. A putative target is the STN (C), overactive in PD by blocking the subthalamic stimulation of GPi and a normalization of downstream thalamocortical connections. Other target could be the indirect pathway from the striatum (D), triggering a dis-repression of SNpr and leading to a normalization of STN activity and therefore a thalamic-cortical neuron well-functioning.

기저핵의 정상 활동과 PD의 오작동에 대한 고전적 모델(참조 [114]에서 검토).

가는 화살표는 하향 조절을, 굵은 화살표는 상향 조절을 나타냅니다. 파란색 화살표는 글루타메이트성 활성화 신경전달물질, 빨간색 화살표는 억제성 가바 신경전달물질, 녹색 화살표는 활성화/억제성 투영을 나타냅니다.

(A) '직접 경로'는 D1 활성 도파민 수용체를 가진 선조체 뉴런과 그 GABAergic 구상돌기가 내측핵(GPi)으로 돌출되어 SNpr이 GABAergic 출력을 통해 억제 신호를 시상 복부 전방(VA) 핵으로 전달하는 것으로 구성됩니다. '간접 경로'는 D2 억제 도파민 수용체를 가진 선조체 뉴런으로 구성됩니다. 선조체(꼬리핵과 퍼타멘으로 구성됨)는 GABAergic 출력을 외측 구상체(GPe)로 투사합니다. 이 지점에서 시상하핵(STN)으로 시냅스가 일어나고, 여기서 글루타메이트 활성화 돌출부가 GPi와 흑질(SNpc/SNpr)에 도달합니다. 시상하핵은 또한 피질로부터 직접 흥분성 입력을 받아 GPi가 VA에서 GABA 방출을 증가시키도록 유도합니다. GPe가 이를 억제하는 동안, SNpc 도파민은 D2 수용체와 결합하여 이 경로를 억제함으로써 GPe에 의한 시상하부 회로의 억제를 차단합니다. 또한 선조체와 SNpc는 신피질로부터 글루타메이트 계열의 신경전달물질을 공급받습니다.

(B) 도파민성 구심성(끊어진 녹색 화살표)의 상실은 선조체 D2 뉴런의 억제를 수반하여 GPe에 대한 가바성 투영의 과잉 활동을 초래하고, 이는 다시 STN에 대한 가바성 구심성 활동을 감소시킵니다. 결과적으로, GPi에 대한 STN 글루타메이터 투영이 과도하게 활성화되어 GPi에서 VA로의 GABAergic 출력이 증가합니다. 반대로, D1 선조체 뉴런은 저활성 상태이므로 GPi 및 SNpr에 대한 GABAergic 출력이 감소하고 결과적으로 두 뉴런에서 VA로의 GABAergic 출력이 증가합니다. 결과적으로 두 경우 모두에서 도파민성 투사의 손실은 시상 피질 출력을 억제하지 못하여 PD의 전형적인 증상인 서동증을 유발합니다.

(C) (D) NMDAR 길항제인 아만타딘과 메만틴의 기저핵 수준에서 가능한 표적. 끊어진 화살표는 출력 투영의 억제를 의미합니다. 추정 표적은 시상하부 자극을 차단하고 하류 시상피질 연결의 정상화를 통해 PD에서 과활성화된 STN(C)입니다. 또 다른 표적은 선조체(D)의 간접 경로로, SNpr의 억제 해제를 유발하여 STN 활동을 정상화함으로써 시상-피질 뉴런이 잘 기능하도록 유도할 수 있습니다.

Accordingly, increased activity of STN neurons has been described in monkeys treated with 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine (MPTP), a neurotoxin that induces parkinsonism in animal models [119], and NMDAR antagonists have been reported to provide potent neuroprotective action [120]. NMDARs localized to the STN also play a role in sustaining pathological hyperactivity observed in a 6-hydroxydopamine rat model of parkinsonism, and the infusion of a NMDAR antagonist into the STN normalized the activity of the basal ganglia [121].

NMDARs are also found on dopaminergic neurons in the SNpc [122]. Increased glutamatergic input to dopaminergic neurons through NMDARs might accelerate the degenerative process [118]. It has been reported that NMDAR antagonists elevate striatal DA release in vivo [123–125] and, given this, would likely be beneficial in PD. In testing this conjecture, the initial class of selective antagonists’ studies in parkinsonism were the phenylethanolamines. One of them, ifenprodil, shows anti-parkinsonian activity in reserpine-treated rats and MPTP-treated monkeys [126].

The effect of an anti-PD medication can be enhanced by NMDAR antagonists. In animal models of PD, NMDAR antagonists have shown a potentiation of the anti-parkinsonian effect of L-dopa and locomotion [109]. Some anticholinergic drugs are also non-competitive antagonists of the NMDAR and, at therapeutic concentrations, may interact with NMDARs and palliate PD [127]. Just as anticholinergics are able to work as NMDA antagonists, NMDA antagonists also can function as anticholinergic agents [128] and normalize the glutamatergic control of corticostriatal ACh release. In the striatum, NMDA stimulation enhances the release of ACh, and antagonists can effectively inhibit this release [110].

Since oxidative products of DA play a role in dopaminergic cell death [129], the use of NMDA antagonists could additionally allow for a decrease in L-dopa dosage and, thereby, diminish any potential oxidative damage. Other NMDA antagonists, such as dextromethorphan, have been reported to suppress dyskinesia in PD patients, but adverse effects (primarily drowsiness) at higher doses would likely limit such a treatment strategy [130]. On the other hand, amantadine (1-amino adamantine) a non-selective NMDA antagonist used to treat PD, provides mild L-dopa-induced anti-dyskinetic benefit with a moderate degree of NMDA antagonist activity [131]. Furthermore, in a large retrospective study, amantadine was associated with an increased lifespan in patients with PD, suggesting that it may have neuroprotective properties [132].

따라서 동물 모델에서 파킨슨병을 유발하는 신경독소인 1-메틸 4-페닐 1, 2, 3, 6-테트라하이드로피리딘(MPTP)으로 치료한 원숭이에서 STN 뉴런의 활동이 증가했으며[119], NMDAR 길항제는 강력한 신경 보호 작용을 제공하는 것으로 보고되었습니다 [120]. STN에 국한된 NMDAR은 또한 6-하이드록시도파민 쥐 파킨슨병 모델에서 관찰된 병적 과잉 활동을 지속시키는 역할을 하며, STN에 NMDAR 길항제를 주입하면 기저핵의 활동이 정상화되었습니다 [121].

NMDAR은 SNpc의 도파민성 뉴런에서도 발견됩니다 [122]. NMDAR을 통해 도파민성 뉴런에 대한 글루탐산 입력이 증가하면 퇴행성 과정이 가속화될 수 있습니다 [118]. NMDAR 길항제는 생체 내에서 선조체 DA 방출을 증가시킨다는 보고가 있으며[123-125], 이를 고려할 때 PD에 도움이 될 수 있습니다. 이러한 추측을 테스트하기 위해 파킨슨병에 대한 선택적 길항제 연구의 초기에는 페닐에탄올아민이 사용되었습니다. 그 중 하나인 이펜프로딜은 레세르핀을 투여한 쥐와 MPTP를 투여한 원숭이에서 항파킨슨 활성을 보였습니다 [126].

항 PD 약물의 효과는 NMDAR 길항제에 의해 향상될 수 있습니다. PD의 동물 모델에서 NMDAR 길항제는 L-도파의 항파킨슨 효과와 운동성을 강화하는 것으로 나타났습니다 [109]. 일부 항콜린성 약물은 또한 NMDAR의 비경쟁적 길항제이며, 치료 농도에서 NMDAR과 상호 작용하여 PD를 완화시킬 수 있습니다 [127]. 항콜린제가 NMDA 길항제로 작용할 수 있는 것처럼, NMDA 길항제도 항콜린제로서 기능할 수 있으며[128], 코르티코스트리아탈 ACh 방출의 글루탐산염 조절을 정상화할 수 있습니다. 선조체에서 NMDA 자극은 ACh의 방출을 향상시키고 길항제는 이 방출을 효과적으로 억제할 수 있습니다 [110].

DA의 산화 생성물은 도파민성 세포 사멸에 중요한 역할을 하기 때문에[129], NMDA 길항제를 사용하면 L-도파 용량을 추가로 감소시켜 잠재적인 산화적 손상을 줄일 수 있습니다. 덱스트로메토르판과 같은 다른 NMDA 길항제는 PD 환자의 운동 이상증을 억제하는 것으로 보고되었지만 고용량에서의 부작용(주로 졸음)으로 인해 이러한 치료 전략이 제한될 가능성이 있습니다[130]. 반면에 PD 치료에 사용되는 비선택적 NMDA 길항제인 아만타딘(1-아미노 아다만틴)은 중간 정도의 NMDA 길항제 활성으로 가벼운 L-도파에 의한 이상운동증 효과를 제공합니다 [131]. 또한 대규모 후향적 연구에서 아만타딘은 파킨슨병 환자의 수명 연장과 관련이 있으며, 이는 신경 보호 특성이 있을 수 있음을 시사합니다 [132].

Memantine Treatment for Parkinson’s Disease

Given that memantine carries out its therapeutic action by targeting the glutamatergic transmission, and the role of NMDARs in basal ganglia for the development of PD symptoms, memantine has also been tested in parkinsonian patients with a degree of moderate success.

Although memantine’s chemical structure is related to amantadine’s, and they act in a somewhat similar pharmacological fashion, memantine does not appear to share the anti-dyskinetic activity of amantadine [133]. However, like DA agonists and other NMDA antagonists, memantine is able to reverse neuroleptic-induced catalepsy [134].

Using patch-clamp techniques, it has been reported that memantine blocks the NMDA ion channel [135], binds to the MK-801 binding site of the NMDAR [136], and decreases NMDA-induced membrane currents. The mechanism of action postulated is a normalization of the corticostriatal glutamatergic activity and/or the subthalamopallidal pathways that are overactive in PD (see Fig. 4C and D). Contrasting with amantadine, in which anti-dyskinetic activity could be rationalized by blocking subthalamic activity, the anti-parkinsonian and synergistic effect of memantine could be due to the inhibition of glutamatergic transmission in the striatum, whereby striatonigral neurons are GABAergic and inhibitory, causing a decreased inhibition of nigrostriatal dopaminergic neurons in SNpc and thereby an elevation in DA release [137].

To investigate the primary efficacy of memantine, a double-blind crossover exploratory trial was designed [133], in which 12 patients with idiopathic PD were randomized to memantine or placebo during two weeks in an escalated dosage from 10 mg/day to 30 mg/day at day 7, and after this time, a single dose of L-dopa was administrated to each arm. Five patients were taking concomitant PD medication (but not amantadine). As expected, a clear anti-parkinsonian activity was observed in terms of counteracting bradykinesia and resting tremor. A synergistic enhancement of L-dopa and memantine seemed evident with motor function. Side effects, mainly drowsiness and nausea, occurred with a similar frequency in both groups.

To further assess the efficacy of memantine, a randomized controlled study was performed with patients suffering from dementia with Lewy bodies or PD dementia that resulted in an improvement in the majority of variables stated in the clinical global impression of change test for the memantine group compared to placebo [138, 139] and a better response assessed in other useful rating scales [140], while the proportion of adverse events was similar to placebo and improved L-dopa-related dyskinesia and the “off” effect [141].

파킨슨병에 대한 메만틴 치료

메만틴이

글루탐산 전달을 표적으로 하여 치료 작용을 하고,

기저핵에서 NMDAR이 파킨슨병 증상을 일으키는 역할을 한다는 점을 고려할 때,

메만틴은 파킨슨병 환자에게도

어느 정도의 성공을 거둔 바 있습니다.

메만틴의 화학 구조는

아만타딘과 관련이 있고

약리학적으로 다소 유사한 방식으로 작용하지만,

메만틴은 아만타딘의 항운동 이상 활성을 공유하지 않는 것으로 보입니다 [133].

그러나

DA 작용제 및 기타 NMDA 길항제와 마찬가지로

메만틴은 신경 이완제로 인한 탈력증을 역전시킬 수 있습니다 [134].

패치 클램프 기술을 사용하여

메만틴은 NMDA 이온 채널을 차단하고[135],

NMDAR의 MK-801 결합 부위에 결합하며[136],

NMDA에 의한 막 전류를 감소시키는 것으로 보고되었습니다.

작용 메커니즘은

PD에서 과활성 상태인 피질질 글루탐산염 활성 및/또는

시상하부 구상체 경로의 정상화라고 가정합니다( 그림 4C 및 D 참조).

시상하부 활동을 차단함으로써

항운동장애 활성을 합리화할 수 있는 아만타딘과 달리,

메만틴의 항파킨슨 및 시너지 효과는

선조체의 글루탐산염 전달을 억제함으로써

선조체 뉴런이 GABAergic 및 억제성이어서

SNpc에서 흑질 도파민성 뉴런의 억제가 감소하고

이로 인해 DA 방출이 상승하기 때문일 수 있습니다 [137].

메만틴의 일차 효능을 조사하기 위해 이

중 맹검 교차 탐색 시험[133]을 설계하여

특발성 PD 환자 12명을

2주 동안 메만틴 또는 위약으로 무작위 배정하여

7일째에 10 mg/일에서 30 mg/일로 용량을 증량하고

그 후 각 군에 L-dopa를 단일 용량으로 투여하는 방식으로 시험을 진행했습니다.

5명의 환자는

아만타딘이 아닌 다른 PD 약물을 병용하고 있었습니다.

예상대로 서동증과 안정 시 떨림에 대응하는 측면에서

명확한 항파킨슨 작용이 관찰되었습니다.

L-도파와 메만틴의 시너지 효과로

운동 기능이 향상되는 것이 분명해 보였습니다.

주로 졸음과 메스꺼움 등의 부작용은

두 그룹에서 비슷한 빈도로 발생했습니다.

메만틴의 효능을 추가로 평가하기 위해

루이체 또는 PD 치매를 앓고 있는 치매 환자를 대상으로 무작위 대조 연구를 수행한 결과,

메만틴 그룹은 위약에 비해

임상 글로벌 변화 인상 테스트에서 대부분의 변수가 개선되었고[138, 139]

다른 유용한 평가 척도에서 평가된 반응이 더 좋았으며[140],

부작용 비율은 위약과 비슷했고

L-dopa 관련 이상운동증과 “오프” 효과가 개선되었습니다[141].

CONCLUDING REMARKS

Several studies show how memantine positively impacts cognition and, hence, they lend credence to the hypothesis that neurotoxicity of glutamatergic overstimulation is involved in dementia. The neuroprotective properties of memantine have also been demonstrated in several in vitro experimental settings, albeit further studies are needed to examine whether memantine treatment and cholinergic treatments could ultimately prove to be complementary or even synergistic. Memantine has also shown efficacy in PD, revealing itself as a potentially promising new therapeutic option. Importantly, as memantine treatment is generally well tolerated, combining it with other therapies is a valuable and feasible option both with AD and PD. However, although memantine was approved for treating mild to moderate AD, its results are modest; therefore, a second generation of adamantane-based drugs are being designed in the hope of improving its clinical efficacy. In conclusion, given the wealth of data on NMDAR activity in AD, VD, and PD, memantine and other drugs that emerge in the NMDAR antagonist class are likely to have an increasingly significant role to play in the future treatment of these diseases.

결론

여러 연구에서 메만틴이 인지에 긍정적인 영향을 미치며, 

따라서 글루탐산 과자극의 신경 독성이 치매에 관여한다는 가설에 신빙성을 부여합니다. 

메만틴의 신경 보호 특성은 

여러 시험관 내 실험 환경에서도 입증되었지만, 

메만틴 치료와 콜린성 치료가 

궁극적으로 상호 보완적이거나 시너지 효과를 낼 수 있는지에 대해서는 

추가 연구가 필요합니다. 

메만틴은 

파킨슨병에도 효능을 보여 

잠재적으로 유망한 새로운 치료 옵션으로 떠오르고 있습니다. 

중요한 것은 

메만틴 치료는 

일반적으로 내약성이 우수하기 때문에 

다른 치료법과 병용하는 것이 

알츠하이머병과 파킨슨병 모두에서 가치 있고 

실현 가능한 옵션이라는 점입니다. 

그러나 

메만틴은 

경증에서 중등도 AD 치료제로 승인되었지만 

그 결과는 미미하기 때문에 임상 효능을 개선하기 위해 

2세대 아다만탄 기반 약물이 설계되고 있습니다. 

결론적으로, 

알츠하이머병, 혈관성 치매, 파킨슨병에서 

NMDAR 활성에 대한 풍부한 데이터를 고려할 때, 

메만틴과 NMDAR 길항제 계열의 다른 약물은 

향후 이러한 질환의 치료에 점점 더 중요한 역할을 할 것으로 보입니다.

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Acknowledgments

This work was supported in part by Radiology Department of Brigham and Women’s Hospital (BWH) and the Intramural Research Program, National Institute on Aging (NIA). Jack T. Rogers is a recipient of Zenith Fellows award of Alzheimer’s Association. We want to thank Ms. Kim Lawson at BWH Radiology Department for her editing of our manuscript. This work was also supported by Grants from Alzheimer’s Association and NIH to DKL.

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LIST OF ABBREVATIONS

Ach	Acetylcholine
AD	Alzheimer’s disease
ADDLs	Aβ-derived diffusible ligands
Amantadine	1-Amino adamantine
AMPA	α-Amino 3-hydroxy 5-methyl 4-isoxazolepropionic acid
APP	Amyloid precursor protein
Aβ	Beta amyloid peptide
BBB	Blood-brain barrier
CNS	Central nervous system
DA	Dopamine
FAD	Familial Alzheimer’s disease
GABA	γ-Aminobutyric acid
GPe	Globus pallidus externus
GPi	Globus pallidus internus
L-dopa	L-dihydroxyphenylalanine
LTP	Long-term potentiation
Memantine	1-Amino-3,5-dimethyladamantane
MPTP	1-Methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine
NFTs	Neurofibrillary tangles
NMDA	N-Methyl D-Aspartate
NOS and NO	Nitric oxide synthase and nitric oxide
PCP	Phencyclidine
PD	Parkinson’s disease
PS1 and PS2	Presenilin-1 and Presenilin-2 protein
SNpc	Substantia nigra pars compacta
SNpr	Substantia nigra pars reticulate
STN	Subthalamic nucleus
VD	Vascular dementia

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Footnotes

CONFLICT OF INTEREST

The authors declare that they do not have any conflicts of interest.

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Curr Alzheimer Res. Author manuscript; available in PMC 2016 Aug 28.

Published in final edited form as:

Curr Alzheimer Res. 2012 Jul; 9(6): 746–758.

doi: 10.2174/156720512801322564

PMCID: PMC5002349

NIHMSID: NIHMS738367

PMID: 21875407

N-Methyl D-Aspartate (NMDA) Receptor Antagonists and Memantine Treatment for Alzheimer’s Disease, Vascular Dementia and Parkinson’s Disease

David Olivares,1 Varun K. Deshpande,2 Ying Shi,2 Debomoy K. Lahiri,3 Nigel H. Greig,4 Jack T. Rogers,5 and Xudong Huang2,5,*

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The publisher's final edited version of this article is available at Curr Alzheimer Res

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Abstract

Memantine, a partial antagonist of N-methyl-D-aspartate receptor (NMDAR), approved for moderate to severe Alzheimer’s disease (AD) treatment within the US and Europe under brand name Namenda (Forest), Axura and Akatinol (Merz), and Ebixa and Abixa (Lundbeck), may have potential in alleviating additional neurological conditions, such as vascular dementia (VD) and Parkinson’s disease (PD). In various animal models, memantine has been reported to be a neuroprotective agent that positively impacts both neurodegenerative and vascular processes. While excessive levels of glutamate result in neurotoxicity, in part through the over-activation of NMDARs, memantine—as a partial NMDAR antagonist, blocks the NMDA glutamate receptors to normalize the glutamatergic system and ameliorate cognitive and memory deficits. The key to memantine’s therapeutic action lies in its uncompetitive binding to the NMDAR through which low affinity and rapid off-rate kinetics of memantine at the level of the NMDAR-channel preserves the physiological function of the receptor, underpinning memantine’s tolerability and low adverse event profile. As the biochemical pathways evoked by NMDAR antagonism also play a role in PD and since no other drug is sufficiently effective to substitute for the first-line treatment of L-dopa despite its side effects, memantine may be useful in PD treatment with possibly fewer side effects. In spite of the relative modest nature of its adverse effects, memantine has been shown to provide only a moderate decrease in clinical deterioration in AD and VD, and hence efforts are being undertaken in the design of new and more potent memantine-based drugs to hopefully provide greater efficacy.

Keywords: Alzheimer’s disease, Parkinson’s disease, vascular dementia, memantine, NMDAR, amantadine

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INTRODUCTION

Alzheimer’s disease (AD), a neurodegenerative disorder characterized by irreversible, progressive loss of memory followed by complete dementia, is marked by cognitive decline accompanied by impaired performance of daily activities, behavior, speech and visual-spatial perception. It is the most common type of dementia among people older than 65, accounting for about 60%-70% of cases [1], associated with heterogeneous risks including genetic, epigenetic, dietary, and lifestyle factors [2].

The most striking and early symptom of AD is a loss of short-term memory (amnesia). When AD is suspected, the diagnosis is usually confirmed with behavioral assessments and cognitive tests, often followed by a brain scan. As the disorder progresses, cognitive impairment includes difficulty in producing or comprehending spoken or written language (aphasia), difficulty of execution of movements (apraxia), loss of perception (agnosia) [3], and disorientation [4]. AD may also involve behavioral changes, such as outbursts of violence or excessive passivity in people who have no previous history of such behavior [5, 6]. Gradually, basic physiological functions are lost, ultimately leading to death.

AD afflicts at least 26 million people throughout the world [7] of which 5.4 million are Americans [8]. In the US, in 2011, it is estimated that at least $183 billion will be spent on direct AD care [8] and these costs will rise as the population ages. Several FDA-approved drugs are currently in use for the treatment of AD, however they mostly bring symptomatic relief and do not cure AD. Such an absence of treatment options sets the stage for the present review, which is primarily focused on the physiological role and utility of NMDAR antagonists, especially memantine, and its treatment not only for AD but other neurodegenerative disorders also, such as Vascular Dementia (VD) and Parkinson’s Disease (PD). The present review summarizes the recent advances in pathogenic processes underlying these diseases, including the amyloid pathway, pharmacology of NMDARs, glutamatergic transmission and the utility of NMDAR antagonists for therapy. Keeping the current interest of the field in mind, we will place a special emphasis on memantine treatment. It is worth mentioning that several aspects of memantine, such as its molecular basis [9], pharmacology [10] and clinical trials [11] have been previously discussed in this journal. However, the present review brings forward distinctly the unique role of memantine in treating AD, VD and PD in a comprehensive manner.

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ALZHEIMER’S DISEASE PATHOGENESIS, NMDARS AND MEMANTINE TREATMENT

Alzheimer’s Disease Pathology and NMDARs

Cognitive impairment in AD is caused, in large part, by the death of cholinergic neurons in the basal forebrain area [12]. Therefore, well characterized in the AD brain are a deficit in acetylcholine (ACh) and classical cholinergic markers, epitomized by choline acetyltransferase and acetylcholineseterase [2, 13].

AD neuropathology is routinely characterized by the accumulation of insoluble amyloid protein that originates from the amyloidogenic processing of a much larger metalloprotein – amyloid precursor protein (APP) [14] that leads to the formation of extracellular neuritic amyloid plaques containing the peptide- beta amyloid peptide (Aβ, see Fig. 1). The other major pathological hallmarks include neurofibrillary tangles (NFTs) that are comprised of misfolded, abnormally phosphorylated microtubule-associated tau protein [15], inflammatory changes with astrocytosis and microgliosis [16], oxidative stress [17, 18] and neuropil threads that have been found in the post-mortem AD brain [19], and in addition, a variety of other neurochemical and cellular alterations that result in anatomic as well as functional impairment of the neurotransmitter systems.

Fig. (1)

Schematic illustration of APP protein and its Aβ product after cleavage by α-, β- and γ-secretases. β- and γ-secretase cleaves on the N- and C-terminal ends of the Aβ region respectively. γ-Secretase cleavage yields a 39–43 amino acid product. Long and more fiblillogenic 42–43 amino acid Aβ species are implicated in AD pathogenesis and may seed the formation of Aβ40 fibrils. Mutations in the APP gene and in genes encoding proteins known as presenilins increase the production of long Aβ. Presenilins-1 and −2 is thought function as γ-secretases (for a review, see [142]).

Although genetic, biochemical and neuropathological data strongly point to Aβ and amyloid plaque formation as a central event in AD pathogenesis [20], the etiopathology of AD remains unclear. A considerable weight of data suggests that it is polygenic and multifactorial [21] and that, likely, Aβ metabolism is sensitive to a range of influences and multiple mechanisms that can cause a shift towards the pathogenic pathways that lead to AD [22]. A small fraction of patients develop AD before the age of 65 known as early onset familial AD (FAD) that is believed to be caused by ~200 mutations in one of three genes: APP (on chromosome 21), and presenilin-1 and −2 (PS1, PS2) (31, 177 and 14 mutations, respectively) [http://www.molgen.ua.ac.be/ADMutations]. A commonality of these numerous mutations is that they, albeit via different routes, increase generation of Aβ and, in particular, the ratio of Aβ42: Aβ40 [23]. Major evidence indicates that soluble aggregates of Aβ and Aβ-derived diffusible ligands (ADDLs) target synapses and impair memory and also can induce cellular dysfunction. Recently, it has been suggested that APP proteolysis generates additional fragments that contribute to neuronal dysfunction [24].

Aβ40 (40 amino acid residues) is the main soluble Aβ species that is found in the cerebrospinal fluid at low nanomolar concentrations [25]. Aβ42 (42 residues) is a minor Aβ species that is more fibrillogenic than Aβ40 and heavily enriched in interstitial plaque amyloid [26]. It is generally agreed that Aβ peptide neurotoxicity is dependent on its conformational state [27]. The in vitro solubility of synthetic Aβ42, in neutral aqueous solutions is lower than Aβ40, consequent to the hydophobicity of the additional carboxylterminal amino acids. Also, it has been demonstrated that soluble Aβ40 can be destabilized through seeding with Aβ42 fibrils [28]. However, the presence or overproduction of Aβ42 alone appears to be insufficient to initiate Aβ amyloid deposition. Overexpression‎ of APP and consequential Aβ overproduction in transgenic mice models rarely results in mice bearing full-blown Alzheimer’s-like neuropathology [29]. Rather, it appears more likely that additional neurochemical factors are required for Aβ amyloidosis.

Some of the potential disease-modifying treatments for AD include NMDAR blockade, use of P-sheet breakers, antioxidant strategies, Aβ-peptide vaccination, secretase inhibitors, APP synthesis inhibitors, cholesterol-lowering drugs, metal chelators and anti-inflammatory agents. Strategies targeting the Aβ protein directly include anti-Aβ immunization, γ- and P-secretase inhibitors, aggregation inhibitors and copper/zinc chelators. Interest in the use of metal chelator drugs stems from recent research suggesting that Aβ plaque formation relies upon the binding of metal ions [22]. Cholinergic drugs such as donepezil, rivastigmine and galantamine represent primary treatments for AD and are based on increasing available levels of ACh to surviving neurons. However, they have not been shown to prevent neuronal death [30] or disease progression [31]. Therefore, the eval‎uation of potential AD treatments that target other mechanisms is a major focus of current investigation and offers the greatest potential to enhance clinical management.

Considerable evidence supports the role of dysregulated glutamate in the pathophysiology of neurodegenerative disorders and excitotoxicity [32]. Therefore, glutamate NMDARs have emerged as key therapeutic targets for AD.

Glutamate is the main excitant neurotransmitter in the mammalian brain, implicated in the excitatory postsynaptic transmission through several ionotropic and metabotropic glutamate receptors. There are three classes of glutamategated channels and a group of G-protein coupled glutamate receptors (which cause mobilization of Ca2+ from internal stores) [33, 34] named according to their activating synthetic agonist: the α-amino 3-hydroxy 5-methyl 4-isoxazole-propionic acid (AMPA) activated receptors, kainate activated receptors, and the N-methyl D-aspartate (NMDA) receptors, have great importance in long-term adaptive processes [35]. Among these, the ion channels coupled to classical NMDARs are generally the most permeable to Ca2+ [36], that can in turn function as a second messenger in various signaling pathways.

NMDA glutamate receptors are abundant and ubiquitously distributed throughout the central nervous system (CNS), playing a critical role in synaptic plasticity and the cellular processes that underlie learning and memory [37]. Long-term potentiation (LTP) is a representation of neuronal synaptic plasticity that consists of a brief induction phase that elicits a long-lasting enhancement in signal transmission between two neurons. A stimulus into a presynaptic cell releases neurotransmitters, mostly glutamate, onto the postsynaptic cell membrane. There, glutamate binds to AMPA receptors in the postsynaptic membrane and triggers the influx of positively charged Na+ ions into the postsynaptic cell, causing a short-lived depolarization called excitatory postsynaptic potential. In synapses that exhibit NMDAR-dependent LTP, sufficient depolarization plus binding of glutamate can unblock NMDARs and relieve the Mg2+ blockade of the NMDAR [38] allowing Ca2+ to flow into the cell.

NMDARs are tetrameric complexes (see Fig. 2) composed by two NR1 subunits (eight splice isoforms, see Fig. 3) that form the channel itself, and two NR2A, NR2B, NR2C or NR2D subunits (derived from four independent genes) [39]. NR2 subunits modulate the characteristics of the NR1 channel; therefore each combination shows different physiological and pharmacological properties [34]. For example, in vitro recombinant NMDARs composed by NR1 and NR2B subunits result in much more sensitivity to the non-competitive antagonist ifenprodil than the NR1/NR2A combination [40]. Recently, NR3 subunits have been found [41], although NR1/NR3A or NR1/NR3B complexes are not activated by glutamate but rather elicit an excitatory response through glycine activation that is independent of Ca2+ influx. Glycine is a mandatory co-factor with glutamate for NMDA channel opening [42] for binding sites onto NR1 and NR2 subunits, respectively, although a more potent inducer than glycine, an uncommon amino acid, D-serine, has been found [43].

Fig. (2)

Depiction of the tetrameric NMDAR at rest (right) and activated after depolarization and binding of agonists glycine and glutamate, suppressing the magnesium channel blockade (left), where antagonists MK-801 and memantine have their allosteric binding site.

Fig. (3)

Schematic structure of eight NR1 receptor isoforms (NR1A–H). Exons 5, 21 and 22 encode three splice cassettes named N1, C1 and C2. Carboxy-terminals variants are generated by splicing out of cassettes C1 and/or C2; and amino-terminal variant, by splicing out of N1. If C2 is excised, the first stop codon is suppressed, resulting in a new open reading frame that encodes the sequence named C2’ [143].

NMDARs have been implicated as a mediator of neuronal injury associated with many neurological disorders including ischemia, epilepsy, brain trauma, dementia, and neurodegenerative disorders, such as PD [44]. Pathological elevations of glutamate levels and possibly other disturbances that alter resting membrane potential (e.g. impaired metabolism) can cause over-stimulation of the NMDAR that can lead to cellular dysfunction and death [45]. Under normal conditions of synaptic transmission, the NMDAR channel is blocked by Mg2+ sitting within the channel and only activated for brief periods of time. However, under pathological conditions, the normal block of the ion channel by Mg2+ is removed and abnormally enhances NMDAR activity [46]. Over-activation of the receptor causes an excessive amount of Ca2+ influx into a neuron to then trigger a variety of processes that can lead to necrosis or apoptosis [47]. The latter process includes Ca2+ overload of mitochondria and the activation of caspases and Ca2+-dependent activation of neuronal nitric oxide synthase (nNOS), leading to increased nitric oxide (NO) production [48]. Mitochondrial Ca2+ overload disables the membrane electrochemical gradient and, therefore, the ATP synthesis [49]. In addition, as consequence of electron chain failure, there is an excessive reactive oxygen species (ROS) production, such as the superoxide anion (O2−) that reacts with NO producing peroxynitrite (ONOO−) that can in turn oxidize lipids, proteins and DNA [50]. Interestingly, Ca2+-triggered neurotoxicity depends on the activation of a determinate pathway, since Ca2+ influx through L-type voltage-gated channels or non-NMDA receptors was not toxic to cells, while a similar Ca2+ load via NMDRs was neurotoxic [51]. Increased activity of nNOS is also associated with excitotoxic cell death [52]. The nNOS is physically tethered to NMDAR through the postsynaptic density protein of 95 kDa (PSD-95) [53] and is activated by Ca2+ entry via calmodulin [41]. In fact, increased levels of NO have been detected in animal models of stroke and neurodegenerative diseases [54, 55]. It has been shown that in PSD-95 mutant mice, the production of NO induced by Ca2+ entry via NMDR is blocked without affecting nNOS expression‎, indicating the specificity of NMDAR in neurotoxicity [53].

Importantly, elevations in extracellular glutamate are not necessary to invoke an excitotoxic mechanism. Excitotoxicity can come into play even with normal levels of glutamate if NMDAR activity is increased, e.g. when neurons are injured and, thus, become depolarized [56]. Much evidence shows that the AD pathogenic cascade includes an excitotoxic component. Application of Aβ has been shown to promote endocytosis of NMDARs in cortical neurons [57]. However, the specific effects of Aβ on excitotoxicity are not yet fully understood, and the exact role of NMDAR activation in AD remains unclear, although several studies have evidenced that Aβ could bind to NMDAR and increase Ca2+ influx into the cell [58].

Many potential neuroprotective agents block virtually all NMDAR activity and therefore, have unacceptable adverse effects, such as psychosis, nausea, vomiting, and a state called dissociative anesthesia, marked by catalepsy, amnesia, and analgesia. Neuronal cell death may accompany complete NMDAR blockade that may occur with high binding affinity of some drugs towards NMDARs [59]. Such possibilities dramatize the crucial role of the NMDAR in normal neuronal processes and explain why many NMDAR antagonists have disappointingly failed to advance in clinical trials for a number of neurodegenerative diseases. To be clinically acceptable, an anti-excitotoxic therapy must block excessive activation of the NMDAR while leaving normal function relatively intact to also avoid side effects. Drugs that simply compete with glutamate for the agonist binding site and block normal physiological functions do not meet this requirement. Both competitive glutamate and glycine antagonists, even although effective in preventing glutamate -mediated neurotoxicity, cause generalized inhibition of NMDAR activities [60]. Non-competitive antagonists, like MK-801, is an effective suppressor of excitotoxicity that acts allosterically (i.e. its binding site is other than the agonist’s) in the ion channel, but due to its high affinity, slow off-rate kinetics and a lesser voltage-dependent activity, blocks the channel for a clinically unacceptable period of time [60]. Such drugs have thus failed in clinical trials to date because of the development of adverse events occurring when the drugs are administered in their therapeutic range [59].

One mechanistic type of drug that can preferentially block higher, pathological levels of glutamate is an ‘uncompetitive’ antagonist that differs from non-competitive antagonists in that it requires receptor activation by an agonist before it can bind to a separate allosteric binding site. This uncompetitive mechanism of action, unlike competitive or non-competitive antagonists, yields a drug that blocks NMDAR channels preferentially when it is excessively open and prevents an excessive flux of calcium inside the cell [61]. Most importantly, it does not substantially accumulate in the channel to interfere with normal synaptic transmission [60]. Evidence suggests that memantine acts by such a mechanism, given that it is a low, moderate affinity, uncompetitive NMDAR antagonist.

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MEMANTINE TREATMENT FOR ALZHEIMER’S DISEASE

Memantine (1-amino-3,5-dimethyladamantane), an amino-alkyl cyclohexane derivative was first synthesized by Eli Lilly and Company (Indianapolis, IN) and patented in 1968, as documented in the Merck Index, as a derivative of adamantine, an anti-influenza agent. It possesses a three-ring (adamantane) structure with a bridgehead amine (−NH2) that, under physiological conditions, carries a positive charge that binds at or near the Mg2+ site within the NMDAR-associated channel.

Memantine was relatively ineffective at blocking the low levels of receptor activity associated with normal neurological function but becomes increasingly effective at higher concentrations of glutamate associated with over-activation of NMDARs [60]. During normal synaptic activity, NMDA channels are open on average for only several milliseconds, and memantine is unable to act or accumulate within the channels; accordingly, synaptic activity continues largely unabated [56]. During prolonged activation of the receptor, however, as occurs under excitotoxic conditions, memantine becomes a highly effective blocker.

In addition to its low to moderate affinity, memantine blocks/unblocks the NMDAR ion channel with rapid kinetics and high voltage dependency [62]. These properties are thought to underlie the apparent ability of memantine to allow normal physiological function of the receptor while impairing pathological activation. Blocking NMDARs has also been reported to mitigate Aβ-induced degeneration of cholinergic neurons in the rat magnocellular nuclear basalis and in rat hippocampal neurons [63–65]. Preclinical data suggest that NMDAR-mediated excitotoxicity may be linked to the effects of abnormal Aβ deposition in AD. More recently, memantine has been found to lower levels of secreted APP and Aβ peptide levels in neuronal cultures and in APP-Swe+PS1 AD transgenic mice [66, 67]. This is important as Aβ accumulation is the precipitating event in AD that leads to synaptic loss among other pathological features. Aβ is known to alter neuronal structure by mechanisms that involve the NMDARand inhibition of the NMDAR can reduce the toxic effects of Aβ.

As a currently approved drug, memantine is indicated for the symptomatic treatment of moderate to severe AD, and has been associated with a moderate decrease in clinical deterioration in AD [68]. Its usefulness has been proved in several clinical trials in which it has shown little but statistically significant improvements [69–72], also assessed by brain imaging [73]. Several systematic reviews of randomized controlled trials have established that memantine has small but helpful actions on cognition, mood, behavior, and the ability to perform daily activities in moderate to severe AD [74–76] nevertheless, the action of the drug in mild to moderate AD remains largely unknown. Importantly, memantine appears capable of achieving its pharmacological actions in a clinically well-tolerated manner and does not show the adverse effects typically associated with high-affinity NMDA-blockers. In trials reporting adverse effects, the primary memantine-induced adverse actions found were infrequent and comparable to placebo such as dizziness, occasional restlessness/agitation, constipation, ocular effects (cataracts, conjunctivitis), nausea, dyspnea, confusion, headache, fatigue, rash, diarrhea and urinary incontinence [77, 78]. On the basis of successful clinical trials, the use of memantine in the modulation of glutamatergic function may therefore represent a useful strategy for the treatment of AD. Furthermore, in vitro and clinical data indicate no adverse interactions between the approved cholinesterase inhibitors and memantine [79, 80].

Because memantine has exhibited efficacy and safety in placebo-controlled trials in patients with moderate to severe AD, the combination of memantine and various cholinesterase inhibitors appears well tolerated and they seem act synergistically due to their distinct mechanisms of action [81–85].

At present, a series of second generation memantine derivatives are currently in development and may have even greater neuroprotective properties than memantine [9, 86]. Whether and how these drugs translate to clinical medicine are awaited with interest.

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MEMANTINE TREATMENT FOR VASCULAR DEMENTIA

Memantine has also been described as effective and well tolerated for the treatment of mild to moderate VD in several randomized clinical trials [87–89]. VD ranks second in preval‎ence as a form of dementia after AD [1], and they often co-exist. It is not infrequent that confusion can occur between both disorders, due to the similarity of their clinical symptoms. VD is a degenerative cerebrovascular disease that leads to a progressive decline in memory and cognitive functioning. The root of this issue relates to a chronic reduced cerebral blood flow (vascular insufficiency) carrying oxygen and nutrients to the brain that may be impaired by a strategic infarct (ischemia) or small (silent) multi-infarcts, hemorrhagic cerebrovascular disease, or can derive from small vessel disease (including lacunar lesions and Binswanger’s disease) [90]. Apart from acute ischemia from embolic or atherothrombotic large vessels occlusion, ischemic-hypoxic brain lesions also can be originated by cardiovascular diseases, such as hypertension or diabetes, which cause a narrowing of the lumen of small vessels [91]. In addition, senile arteriolosclerosis produces tortuosity and elongation of arterioles [92].

Since it may be partly preventable, VD needs to be differentiated from other causes of dementia such as AD, Lewy body-type dementia and PD. Special attention has to be given when attempting to make a differential diagnosis, to the following steps that may lead to a diagnosis of VD [93]:

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Oxygen and glucose deprivation are followed by an elevation of extracellular glutamate both in ischemic brain damage and traumatic brain injury [50] that results in consequent NMDR overactivation and massive Ca2+ influx. Failure of astrocyte functions also has been reported [94] such as maintenance of blood-brain barrier (BBB) cells in cerebral microvasculature and endothelial permeability [95]. Disruption of tight junctions among endothelial cells, degradation of the basal lamina and extracellular matrix by metalloproteinases-2 and −9 are involved in BBB breakdown and cerebral hemorrhagia [96–98]. In addition, adhesion and transmigration of leukocyte occurs, leading to activation of an inflammatory response [99]. For a review of downstream processes after calcium entry in ischemia, see Ref. [48].

In general, cerebral lesions after ischemic injury begin with an initial reversible stage where neurons finally become necrotic [100]. The cells of the ischemic core undergo anoxic depolarizations that expand to the penumbral region and a lack of energy that leads to necrosis [101]. Since the ischemic area grows as the number of peri-infarct depolarizations increases, the extension of severe damaged area can be attenuated by blocking NMDAR-mediated depolarizations [102].

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PARKINSON’S DISEASE PATHOGENESIS, NMDARS, GLUTAMATERGIC TRANSMISSION AND MEMANTINE TREATMENT

Parkinson’s Disease Pathology, NMDARs and Glutamatergic Transmission

PD is the second most frequent progressive-type neurodegenerative disorder after AD [103] and represents, like AD, a large health burden to society. Approximately 1% of the population over 60 years of age is affected [104]. Classical clinical symptoms include tremors; bradykinesia, or slowness of movement; and rigidity, or akinesia.

The primary underlying pathology of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) that innervates the striatum. At post-mortem examination, the depletion frequently exceeds 90% [105] with consequent loss of neuronal systems responsible for motor functions. Besides, cell death is not limited to dopaminergic neurons in SNpc and can expand to other areas of the brain, leading to extensive neuronal death. It is not infrequent to find dementia in patients afflicted by PD. A further archetypal hallmark is the formation of intracytoplasmic inclusions, termed Lewy bodies, in remaining neurons [106].

To date, no curative treatment for PD exists but symptomic control can be achieved. The most effective treatments are based on the replacement of dopamine (DA) loss using either the precursor of DA, L-dihydroxyphenylalanine (L-dopa), or agonist-mediated stimulators of DA receptors, epitomized by pramipexole or ropinirole. Essentially, all patients require L-dopa at some stage of disease progression, in spite of its adverse effects, such as the “wearing-off” phenomenon – relating to the shortening of sustainable pharmacological activity [107] as occurs when the symptoms of PD, attenuated by the treatment, become more intense prior to the next expected dose. Albeit that L-dopa is associated with dyskinesia or diminished voluntary movements and the presence of involuntary movements, it must be recognized that, since L-dopa’s clinical introduction, survival with PD has been considerably prolonged [108].

NMDARs are very abundant in the striatum [109], comprised by putamen and caudate nucleus, where they regulate the release of neurotransmitters like γ-aminobutyric acid (GABA) and ACh [110]. NMDARs downstream of the striatum also participate in modulating the activities of basal ganglia circuit and are present in the subthalamic nucleus (STN), globus pallidus internus (GPi) [111], and cerebral cortex [112]. The activity of NMDARs is largely regulated by dopaminergic afferents. D1 receptor agonists elicit a fast enhancement of NMDA-induced depolarization of striatal cells, whereas D2 receptor agonists attenuate this [113].

Execution of voluntary movement starts with the cortex (executive) signaling the caudate and putamen via glutamatergic projections or from the SNpc via dopamine. The Striatum then sends inhibitory GABAergic signals to GPi leads to disinhibition of the thalamic ventral anterior (VA). This leads to stimulatory signaling of the motor cortex by the thalamic VA and initiation of movement. As described, PD is characterized by depletion of dopaminergic neurons, leading to a disinhibition of striatal neurons that have inhibitory D2 dopaminergic receptors and project to the globus pallidus externus (GPe), and to a decrease of striatal neuron activity projecting to the GPi and the substantia nigra pars reticulata (SNpr) that have D1 excitatory dopaminergic receptors [114]. All these striatal efferent pathways are mediated by GABA and are inhibitory so that GPe projection to the STN (also inhibitory) is reduced. Therefore, the suppression of dopaminergic modulation disinhibits STN neurons, rendering them overactive [115]. The enhanced activity of excitatory glutamatergic STN projections to GPi and SNpr (besides lack of inhibitory input from the GPe stated above) further enhance the activity of their GABAergic neurons [116]. Spontaneous movement is reduced by inhibiting the activity of thalamic glutamatergic and excitatory VA projections VA to the motor frontal cortex (see Fig. 4A and B). Acetylcholinergic neurons in the brainstem and basal forebrain areas, are regulated by prefrontal cortex glutamatergic projections, and seem to be of special relevance in modulating motor, emotional and mnemonic functions [117], therefore a decrease of thalamocortical input entails a deficit of ACh, leading to a decline in voluntary movements. Likewise, the striatum and SNpc can receive glutamatergic excitatory input from the neocortex [118].

Fig. (4)

Classical model of normal activity of the basal ganglia and malfunctioning in PD (reviewed in Ref. [114]). Thin arrows indicate downregulation and thick arrows upregulation. Blue arrows show glutamatergic activatory efferents, red arrows indicate inhibitory GABAergic efferents and green arrows, activatory/inhibitory projections. (A) The ‘direct pathway’ is comprised of striatal neurons with D1 activatory dopaminergic receptors and their GABAergic efferent projections to the globus pallidus internus (GPi) which together the SNpr transmit inhibitory signals via GABAergic output to the thalamic ventral anterior (VA) nucleus. The ‘indirect pathway’ is comprised of striatal neurons with D2 inhibitory dopaminergic receptors. The striatum (composed of caudate and putamen) projects GABAergic output to the globus pallidus externus (GPe). From this point, they synapse to the nucleus subthalamicus (STN), from which glutamatergic activatory projections reach the GPi and the substantia nigra (SNpc/SNpr). The subthalamic nucleus also gets excitatory input directly from the cortex and induces the GPi to increase GABA release in the VA. While GPe keeps it in check, the SNpc dopamine binds D2 receptors to inhibit this pathway, blocking the inhibition of the subthalamic circuit by GPe. Additionally, the striatum and the SNpc receive glutamatergic efferents from the neocortex.

(B) Loss of dopaminergic afferents (broken green arrows) entails a dis-repression of striatal D2 neurons leads to over-activity of their GABAergic projections to the GPe, and this in turn decreases its GABAergic efferent activity to the STN. As a consequence, STN glutamatergic projections to the GPi render over-active, increasing GABAergic output from the GPi to the VA. On the contrary, the D1 striatal neurons are underactive, therefore the GABAergic output to the GPi and to the SNpr are reduced and consequently the GABAergic output from both to the VA is increased. As a consequence in both cases, the loss of dopaminergic projections causes a failure to desinhibit the thalamocortical output, leading to bradykinesia, a typical symptom in PD. (C) (D) Possible targets at the basal ganglia level of NMDAR antagonists amantadine and memantine. Broken arrows mean suppression of output projections. A putative target is the STN (C), overactive in PD by blocking the subthalamic stimulation of GPi and a normalization of downstream thalamocortical connections. Other target could be the indirect pathway from the striatum (D), triggering a dis-repression of SNpr and leading to a normalization of STN activity and therefore a thalamic-cortical neuron well-functioning.

Accordingly, increased activity of STN neurons has been described in monkeys treated with 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine (MPTP), a neurotoxin that induces parkinsonism in animal models [119], and NMDAR antagonists have been reported to provide potent neuroprotective action [120]. NMDARs localized to the STN also play a role in sustaining pathological hyperactivity observed in a 6-hydroxydopamine rat model of parkinsonism, and the infusion of a NMDAR antagonist into the STN normalized the activity of the basal ganglia [121].

NMDARs are also found on dopaminergic neurons in the SNpc [122]. Increased glutamatergic input to dopaminergic neurons through NMDARs might accelerate the degenerative process [118]. It has been reported that NMDAR antagonists elevate striatal DA release in vivo [123–125] and, given this, would likely be beneficial in PD. In testing this conjecture, the initial class of selective antagonists’ studies in parkinsonism were the phenylethanolamines. One of them, ifenprodil, shows anti-parkinsonian activity in reserpine-treated rats and MPTP-treated monkeys [126].

The effect of an anti-PD medication can be enhanced by NMDAR antagonists. In animal models of PD, NMDAR antagonists have shown a potentiation of the anti-parkinsonian effect of L-dopa and locomotion [109]. Some anticholinergic drugs are also non-competitive antagonists of the NMDAR and, at therapeutic concentrations, may interact with NMDARs and palliate PD [127]. Just as anticholinergics are able to work as NMDA antagonists, NMDA antagonists also can function as anticholinergic agents [128] and normalize the glutamatergic control of corticostriatal ACh release. In the striatum, NMDA stimulation enhances the release of ACh, and antagonists can effectively inhibit this release [110].

Since oxidative products of DA play a role in dopaminergic cell death [129], the use of NMDA antagonists could additionally allow for a decrease in L-dopa dosage and, thereby, diminish any potential oxidative damage. Other NMDA antagonists, such as dextromethorphan, have been reported to suppress dyskinesia in PD patients, but adverse effects (primarily drowsiness) at higher doses would likely limit such a treatment strategy [130]. On the other hand, amantadine (1-amino adamantine) a non-selective NMDA antagonist used to treat PD, provides mild L-dopa-induced anti-dyskinetic benefit with a moderate degree of NMDA antagonist activity [131]. Furthermore, in a large retrospective study, amantadine was associated with an increased lifespan in patients with PD, suggesting that it may have neuroprotective properties [132].

Memantine Treatment for Parkinson’s Disease

Given that memantine carries out its therapeutic action by targeting the glutamatergic transmission, and the role of NMDARs in basal ganglia for the development of PD symptoms, memantine has also been tested in parkinsonian patients with a degree of moderate success.

Although memantine’s chemical structure is related to amantadine’s, and they act in a somewhat similar pharmacological fashion, memantine does not appear to share the anti-dyskinetic activity of amantadine [133]. However, like DA agonists and other NMDA antagonists, memantine is able to reverse neuroleptic-induced catalepsy [134].

Using patch-clamp techniques, it has been reported that memantine blocks the NMDA ion channel [135], binds to the MK-801 binding site of the NMDAR [136], and decreases NMDA-induced membrane currents. The mechanism of action postulated is a normalization of the corticostriatal glutamatergic activity and/or the subthalamopallidal pathways that are overactive in PD (see Fig. 4C and D). Contrasting with amantadine, in which anti-dyskinetic activity could be rationalized by blocking subthalamic activity, the anti-parkinsonian and synergistic effect of memantine could be due to the inhibition of glutamatergic transmission in the striatum, whereby striatonigral neurons are GABAergic and inhibitory, causing a decreased inhibition of nigrostriatal dopaminergic neurons in SNpc and thereby an elevation in DA release [137].

To investigate the primary efficacy of memantine, a double-blind crossover exploratory trial was designed [133], in which 12 patients with idiopathic PD were randomized to memantine or placebo during two weeks in an escalated dosage from 10 mg/day to 30 mg/day at day 7, and after this time, a single dose of L-dopa was administrated to each arm. Five patients were taking concomitant PD medication (but not amantadine). As expected, a clear anti-parkinsonian activity was observed in terms of counteracting bradykinesia and resting tremor. A synergistic enhancement of L-dopa and memantine seemed evident with motor function. Side effects, mainly drowsiness and nausea, occurred with a similar frequency in both groups.

To further assess the efficacy of memantine, a randomized controlled study was performed with patients suffering from dementia with Lewy bodies or PD dementia that resulted in an improvement in the majority of variables stated in the clinical global impression of change test for the memantine group compared to placebo [138, 139] and a better response assessed in other useful rating scales [140], while the proportion of adverse events was similar to placebo and improved L-dopa-related dyskinesia and the “off” effect [141].

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CONCLUDING REMARKS

Several studies show how memantine positively impacts cognition and, hence, they lend credence to the hypothesis that neurotoxicity of glutamatergic overstimulation is involved in dementia. The neuroprotective properties of memantine have also been demonstrated in several in vitro experimental settings, albeit further studies are needed to examine whether memantine treatment and cholinergic treatments could ultimately prove to be complementary or even synergistic. Memantine has also shown efficacy in PD, revealing itself as a potentially promising new therapeutic option. Importantly, as memantine treatment is generally well tolerated, combining it with other therapies is a valuable and feasible option both with AD and PD. However, although memantine was approved for treating mild to moderate AD, its results are modest; therefore, a second generation of adamantane-based drugs are being designed in the hope of improving its clinical efficacy. In conclusion, given the wealth of data on NMDAR activity in AD, VD, and PD, memantine and other drugs that emerge in the NMDAR antagonist class are likely to have an increasingly significant role to play in the future treatment of these diseases.

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Acknowledgments

This work was supported in part by Radiology Department of Brigham and Women’s Hospital (BWH) and the Intramural Research Program, National Institute on Aging (NIA). Jack T. Rogers is a recipient of Zenith Fellows award of Alzheimer’s Association. We want to thank Ms. Kim Lawson at BWH Radiology Department for her editing of our manuscript. This work was also supported by Grants from Alzheimer’s Association and NIH to DKL.

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LIST OF ABBREVATIONS

Ach	Acetylcholine
AD	Alzheimer’s disease
ADDLs	Aβ-derived diffusible ligands
Amantadine	1-Amino adamantine
AMPA	α-Amino 3-hydroxy 5-methyl 4-isoxazolepropionic acid
APP	Amyloid precursor protein
Aβ	Beta amyloid peptide
BBB	Blood-brain barrier
CNS	Central nervous system
DA	Dopamine
FAD	Familial Alzheimer’s disease
GABA	γ-Aminobutyric acid
GPe	Globus pallidus externus
GPi	Globus pallidus internus
L-dopa	L-dihydroxyphenylalanine
LTP	Long-term potentiation
Memantine	1-Amino-3,5-dimethyladamantane
MPTP	1-Methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine
NFTs	Neurofibrillary tangles
NMDA	N-Methyl D-Aspartate
NOS and NO	Nitric oxide synthase and nitric oxide
PCP	Phencyclidine
PD	Parkinson’s disease
PS1 and PS2	Presenilin-1 and Presenilin-2 protein
SNpc	Substantia nigra pars compacta
SNpr	Substantia nigra pars reticulate
STN	Subthalamic nucleus
VD	Vascular dementia

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Footnotes

CONFLICT OF INTEREST

The authors declare that they do not have any conflicts of interest.

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Curr Alzheimer Res. Author manuscript; available in PMC 2016 Aug 28.

Published in final edited form as:

Curr Alzheimer Res. 2012 Jul; 9(6): 746–758.

doi: 10.2174/156720512801322564

PMCID: PMC5002349

NIHMSID: NIHMS738367

PMID: 21875407

N-Methyl D-Aspartate (NMDA) Receptor Antagonists and Memantine Treatment for Alzheimer’s Disease, Vascular Dementia and Parkinson’s Disease

David Olivares,1 Varun K. Deshpande,2 Ying Shi,2 Debomoy K. Lahiri,3 Nigel H. Greig,4 Jack T. Rogers,5 and Xudong Huang2,5,*

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Abstract

Memantine, a partial antagonist of N-methyl-D-aspartate receptor (NMDAR), approved for moderate to severe Alzheimer’s disease (AD) treatment within the US and Europe under brand name Namenda (Forest), Axura and Akatinol (Merz), and Ebixa and Abixa (Lundbeck), may have potential in alleviating additional neurological conditions, such as vascular dementia (VD) and Parkinson’s disease (PD). In various animal models, memantine has been reported to be a neuroprotective agent that positively impacts both neurodegenerative and vascular processes. While excessive levels of glutamate result in neurotoxicity, in part through the over-activation of NMDARs, memantine—as a partial NMDAR antagonist, blocks the NMDA glutamate receptors to normalize the glutamatergic system and ameliorate cognitive and memory deficits. The key to memantine’s therapeutic action lies in its uncompetitive binding to the NMDAR through which low affinity and rapid off-rate kinetics of memantine at the level of the NMDAR-channel preserves the physiological function of the receptor, underpinning memantine’s tolerability and low adverse event profile. As the biochemical pathways evoked by NMDAR antagonism also play a role in PD and since no other drug is sufficiently effective to substitute for the first-line treatment of L-dopa despite its side effects, memantine may be useful in PD treatment with possibly fewer side effects. In spite of the relative modest nature of its adverse effects, memantine has been shown to provide only a moderate decrease in clinical deterioration in AD and VD, and hence efforts are being undertaken in the design of new and more potent memantine-based drugs to hopefully provide greater efficacy.

Keywords: Alzheimer’s disease, Parkinson’s disease, vascular dementia, memantine, NMDAR, amantadine

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INTRODUCTION

Alzheimer’s disease (AD), a neurodegenerative disorder characterized by irreversible, progressive loss of memory followed by complete dementia, is marked by cognitive decline accompanied by impaired performance of daily activities, behavior, speech and visual-spatial perception. It is the most common type of dementia among people older than 65, accounting for about 60%-70% of cases [1], associated with heterogeneous risks including genetic, epigenetic, dietary, and lifestyle factors [2].

The most striking and early symptom of AD is a loss of short-term memory (amnesia). When AD is suspected, the diagnosis is usually confirmed with behavioral assessments and cognitive tests, often followed by a brain scan. As the disorder progresses, cognitive impairment includes difficulty in producing or comprehending spoken or written language (aphasia), difficulty of execution of movements (apraxia), loss of perception (agnosia) [3], and disorientation [4]. AD may also involve behavioral changes, such as outbursts of violence or excessive passivity in people who have no previous history of such behavior [5, 6]. Gradually, basic physiological functions are lost, ultimately leading to death.

AD afflicts at least 26 million people throughout the world [7] of which 5.4 million are Americans [8]. In the US, in 2011, it is estimated that at least $183 billion will be spent on direct AD care [8] and these costs will rise as the population ages. Several FDA-approved drugs are currently in use for the treatment of AD, however they mostly bring symptomatic relief and do not cure AD. Such an absence of treatment options sets the stage for the present review, which is primarily focused on the physiological role and utility of NMDAR antagonists, especially memantine, and its treatment not only for AD but other neurodegenerative disorders also, such as Vascular Dementia (VD) and Parkinson’s Disease (PD). The present review summarizes the recent advances in pathogenic processes underlying these diseases, including the amyloid pathway, pharmacology of NMDARs, glutamatergic transmission and the utility of NMDAR antagonists for therapy. Keeping the current interest of the field in mind, we will place a special emphasis on memantine treatment. It is worth mentioning that several aspects of memantine, such as its molecular basis [9], pharmacology [10] and clinical trials [11] have been previously discussed in this journal. However, the present review brings forward distinctly the unique role of memantine in treating AD, VD and PD in a comprehensive manner.

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ALZHEIMER’S DISEASE PATHOGENESIS, NMDARS AND MEMANTINE TREATMENT

Alzheimer’s Disease Pathology and NMDARs

Cognitive impairment in AD is caused, in large part, by the death of cholinergic neurons in the basal forebrain area [12]. Therefore, well characterized in the AD brain are a deficit in acetylcholine (ACh) and classical cholinergic markers, epitomized by choline acetyltransferase and acetylcholineseterase [2, 13].

AD neuropathology is routinely characterized by the accumulation of insoluble amyloid protein that originates from the amyloidogenic processing of a much larger metalloprotein – amyloid precursor protein (APP) [14] that leads to the formation of extracellular neuritic amyloid plaques containing the peptide- beta amyloid peptide (Aβ, see Fig. 1). The other major pathological hallmarks include neurofibrillary tangles (NFTs) that are comprised of misfolded, abnormally phosphorylated microtubule-associated tau protein [15], inflammatory changes with astrocytosis and microgliosis [16], oxidative stress [17, 18] and neuropil threads that have been found in the post-mortem AD brain [19], and in addition, a variety of other neurochemical and cellular alterations that result in anatomic as well as functional impairment of the neurotransmitter systems.

Fig. (1)

Schematic illustration of APP protein and its Aβ product after cleavage by α-, β- and γ-secretases. β- and γ-secretase cleaves on the N- and C-terminal ends of the Aβ region respectively. γ-Secretase cleavage yields a 39–43 amino acid product. Long and more fiblillogenic 42–43 amino acid Aβ species are implicated in AD pathogenesis and may seed the formation of Aβ40 fibrils. Mutations in the APP gene and in genes encoding proteins known as presenilins increase the production of long Aβ. Presenilins-1 and −2 is thought function as γ-secretases (for a review, see [142]).

Although genetic, biochemical and neuropathological data strongly point to Aβ and amyloid plaque formation as a central event in AD pathogenesis [20], the etiopathology of AD remains unclear. A considerable weight of data suggests that it is polygenic and multifactorial [21] and that, likely, Aβ metabolism is sensitive to a range of influences and multiple mechanisms that can cause a shift towards the pathogenic pathways that lead to AD [22]. A small fraction of patients develop AD before the age of 65 known as early onset familial AD (FAD) that is believed to be caused by ~200 mutations in one of three genes: APP (on chromosome 21), and presenilin-1 and −2 (PS1, PS2) (31, 177 and 14 mutations, respectively) [http://www.molgen.ua.ac.be/ADMutations]. A commonality of these numerous mutations is that they, albeit via different routes, increase generation of Aβ and, in particular, the ratio of Aβ42: Aβ40 [23]. Major evidence indicates that soluble aggregates of Aβ and Aβ-derived diffusible ligands (ADDLs) target synapses and impair memory and also can induce cellular dysfunction. Recently, it has been suggested that APP proteolysis generates additional fragments that contribute to neuronal dysfunction [24].

Aβ40 (40 amino acid residues) is the main soluble Aβ species that is found in the cerebrospinal fluid at low nanomolar concentrations [25]. Aβ42 (42 residues) is a minor Aβ species that is more fibrillogenic than Aβ40 and heavily enriched in interstitial plaque amyloid [26]. It is generally agreed that Aβ peptide neurotoxicity is dependent on its conformational state [27]. The in vitro solubility of synthetic Aβ42, in neutral aqueous solutions is lower than Aβ40, consequent to the hydophobicity of the additional carboxylterminal amino acids. Also, it has been demonstrated that soluble Aβ40 can be destabilized through seeding with Aβ42 fibrils [28]. However, the presence or overproduction of Aβ42 alone appears to be insufficient to initiate Aβ amyloid deposition. Overexpression‎ of APP and consequential Aβ overproduction in transgenic mice models rarely results in mice bearing full-blown Alzheimer’s-like neuropathology [29]. Rather, it appears more likely that additional neurochemical factors are required for Aβ amyloidosis.

Some of the potential disease-modifying treatments for AD include NMDAR blockade, use of P-sheet breakers, antioxidant strategies, Aβ-peptide vaccination, secretase inhibitors, APP synthesis inhibitors, cholesterol-lowering drugs, metal chelators and anti-inflammatory agents. Strategies targeting the Aβ protein directly include anti-Aβ immunization, γ- and P-secretase inhibitors, aggregation inhibitors and copper/zinc chelators. Interest in the use of metal chelator drugs stems from recent research suggesting that Aβ plaque formation relies upon the binding of metal ions [22]. Cholinergic drugs such as donepezil, rivastigmine and galantamine represent primary treatments for AD and are based on increasing available levels of ACh to surviving neurons. However, they have not been shown to prevent neuronal death [30] or disease progression [31]. Therefore, the eval‎uation of potential AD treatments that target other mechanisms is a major focus of current investigation and offers the greatest potential to enhance clinical management.

Considerable evidence supports the role of dysregulated glutamate in the pathophysiology of neurodegenerative disorders and excitotoxicity [32]. Therefore, glutamate NMDARs have emerged as key therapeutic targets for AD.

Glutamate is the main excitant neurotransmitter in the mammalian brain, implicated in the excitatory postsynaptic transmission through several ionotropic and metabotropic glutamate receptors. There are three classes of glutamategated channels and a group of G-protein coupled glutamate receptors (which cause mobilization of Ca2+ from internal stores) [33, 34] named according to their activating synthetic agonist: the α-amino 3-hydroxy 5-methyl 4-isoxazole-propionic acid (AMPA) activated receptors, kainate activated receptors, and the N-methyl D-aspartate (NMDA) receptors, have great importance in long-term adaptive processes [35]. Among these, the ion channels coupled to classical NMDARs are generally the most permeable to Ca2+ [36], that can in turn function as a second messenger in various signaling pathways.

NMDA glutamate receptors are abundant and ubiquitously distributed throughout the central nervous system (CNS), playing a critical role in synaptic plasticity and the cellular processes that underlie learning and memory [37]. Long-term potentiation (LTP) is a representation of neuronal synaptic plasticity that consists of a brief induction phase that elicits a long-lasting enhancement in signal transmission between two neurons. A stimulus into a presynaptic cell releases neurotransmitters, mostly glutamate, onto the postsynaptic cell membrane. There, glutamate binds to AMPA receptors in the postsynaptic membrane and triggers the influx of positively charged Na+ ions into the postsynaptic cell, causing a short-lived depolarization called excitatory postsynaptic potential. In synapses that exhibit NMDAR-dependent LTP, sufficient depolarization plus binding of glutamate can unblock NMDARs and relieve the Mg2+ blockade of the NMDAR [38] allowing Ca2+ to flow into the cell.

NMDARs are tetrameric complexes (see Fig. 2) composed by two NR1 subunits (eight splice isoforms, see Fig. 3) that form the channel itself, and two NR2A, NR2B, NR2C or NR2D subunits (derived from four independent genes) [39]. NR2 subunits modulate the characteristics of the NR1 channel; therefore each combination shows different physiological and pharmacological properties [34]. For example, in vitro recombinant NMDARs composed by NR1 and NR2B subunits result in much more sensitivity to the non-competitive antagonist ifenprodil than the NR1/NR2A combination [40]. Recently, NR3 subunits have been found [41], although NR1/NR3A or NR1/NR3B complexes are not activated by glutamate but rather elicit an excitatory response through glycine activation that is independent of Ca2+ influx. Glycine is a mandatory co-factor with glutamate for NMDA channel opening [42] for binding sites onto NR1 and NR2 subunits, respectively, although a more potent inducer than glycine, an uncommon amino acid, D-serine, has been found [43].

Fig. (2)

Depiction of the tetrameric NMDAR at rest (right) and activated after depolarization and binding of agonists glycine and glutamate, suppressing the magnesium channel blockade (left), where antagonists MK-801 and memantine have their allosteric binding site.

Fig. (3)

Schematic structure of eight NR1 receptor isoforms (NR1A–H). Exons 5, 21 and 22 encode three splice cassettes named N1, C1 and C2. Carboxy-terminals variants are generated by splicing out of cassettes C1 and/or C2; and amino-terminal variant, by splicing out of N1. If C2 is excised, the first stop codon is suppressed, resulting in a new open reading frame that encodes the sequence named C2’ [143].

NMDARs have been implicated as a mediator of neuronal injury associated with many neurological disorders including ischemia, epilepsy, brain trauma, dementia, and neurodegenerative disorders, such as PD [44]. Pathological elevations of glutamate levels and possibly other disturbances that alter resting membrane potential (e.g. impaired metabolism) can cause over-stimulation of the NMDAR that can lead to cellular dysfunction and death [45]. Under normal conditions of synaptic transmission, the NMDAR channel is blocked by Mg2+ sitting within the channel and only activated for brief periods of time. However, under pathological conditions, the normal block of the ion channel by Mg2+ is removed and abnormally enhances NMDAR activity [46]. Over-activation of the receptor causes an excessive amount of Ca2+ influx into a neuron to then trigger a variety of processes that can lead to necrosis or apoptosis [47]. The latter process includes Ca2+ overload of mitochondria and the activation of caspases and Ca2+-dependent activation of neuronal nitric oxide synthase (nNOS), leading to increased nitric oxide (NO) production [48]. Mitochondrial Ca2+ overload disables the membrane electrochemical gradient and, therefore, the ATP synthesis [49]. In addition, as consequence of electron chain failure, there is an excessive reactive oxygen species (ROS) production, such as the superoxide anion (O2−) that reacts with NO producing peroxynitrite (ONOO−) that can in turn oxidize lipids, proteins and DNA [50]. Interestingly, Ca2+-triggered neurotoxicity depends on the activation of a determinate pathway, since Ca2+ influx through L-type voltage-gated channels or non-NMDA receptors was not toxic to cells, while a similar Ca2+ load via NMDRs was neurotoxic [51]. Increased activity of nNOS is also associated with excitotoxic cell death [52]. The nNOS is physically tethered to NMDAR through the postsynaptic density protein of 95 kDa (PSD-95) [53] and is activated by Ca2+ entry via calmodulin [41]. In fact, increased levels of NO have been detected in animal models of stroke and neurodegenerative diseases [54, 55]. It has been shown that in PSD-95 mutant mice, the production of NO induced by Ca2+ entry via NMDR is blocked without affecting nNOS expression‎, indicating the specificity of NMDAR in neurotoxicity [53].

Importantly, elevations in extracellular glutamate are not necessary to invoke an excitotoxic mechanism. Excitotoxicity can come into play even with normal levels of glutamate if NMDAR activity is increased, e.g. when neurons are injured and, thus, become depolarized [56]. Much evidence shows that the AD pathogenic cascade includes an excitotoxic component. Application of Aβ has been shown to promote endocytosis of NMDARs in cortical neurons [57]. However, the specific effects of Aβ on excitotoxicity are not yet fully understood, and the exact role of NMDAR activation in AD remains unclear, although several studies have evidenced that Aβ could bind to NMDAR and increase Ca2+ influx into the cell [58].

Many potential neuroprotective agents block virtually all NMDAR activity and therefore, have unacceptable adverse effects, such as psychosis, nausea, vomiting, and a state called dissociative anesthesia, marked by catalepsy, amnesia, and analgesia. Neuronal cell death may accompany complete NMDAR blockade that may occur with high binding affinity of some drugs towards NMDARs [59]. Such possibilities dramatize the crucial role of the NMDAR in normal neuronal processes and explain why many NMDAR antagonists have disappointingly failed to advance in clinical trials for a number of neurodegenerative diseases. To be clinically acceptable, an anti-excitotoxic therapy must block excessive activation of the NMDAR while leaving normal function relatively intact to also avoid side effects. Drugs that simply compete with glutamate for the agonist binding site and block normal physiological functions do not meet this requirement. Both competitive glutamate and glycine antagonists, even although effective in preventing glutamate -mediated neurotoxicity, cause generalized inhibition of NMDAR activities [60]. Non-competitive antagonists, like MK-801, is an effective suppressor of excitotoxicity that acts allosterically (i.e. its binding site is other than the agonist’s) in the ion channel, but due to its high affinity, slow off-rate kinetics and a lesser voltage-dependent activity, blocks the channel for a clinically unacceptable period of time [60]. Such drugs have thus failed in clinical trials to date because of the development of adverse events occurring when the drugs are administered in their therapeutic range [59].

One mechanistic type of drug that can preferentially block higher, pathological levels of glutamate is an ‘uncompetitive’ antagonist that differs from non-competitive antagonists in that it requires receptor activation by an agonist before it can bind to a separate allosteric binding site. This uncompetitive mechanism of action, unlike competitive or non-competitive antagonists, yields a drug that blocks NMDAR channels preferentially when it is excessively open and prevents an excessive flux of calcium inside the cell [61]. Most importantly, it does not substantially accumulate in the channel to interfere with normal synaptic transmission [60]. Evidence suggests that memantine acts by such a mechanism, given that it is a low, moderate affinity, uncompetitive NMDAR antagonist.

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MEMANTINE TREATMENT FOR ALZHEIMER’S DISEASE

Memantine (1-amino-3,5-dimethyladamantane), an amino-alkyl cyclohexane derivative was first synthesized by Eli Lilly and Company (Indianapolis, IN) and patented in 1968, as documented in the Merck Index, as a derivative of adamantine, an anti-influenza agent. It possesses a three-ring (adamantane) structure with a bridgehead amine (−NH2) that, under physiological conditions, carries a positive charge that binds at or near the Mg2+ site within the NMDAR-associated channel.

Memantine was relatively ineffective at blocking the low levels of receptor activity associated with normal neurological function but becomes increasingly effective at higher concentrations of glutamate associated with over-activation of NMDARs [60]. During normal synaptic activity, NMDA channels are open on average for only several milliseconds, and memantine is unable to act or accumulate within the channels; accordingly, synaptic activity continues largely unabated [56]. During prolonged activation of the receptor, however, as occurs under excitotoxic conditions, memantine becomes a highly effective blocker.

In addition to its low to moderate affinity, memantine blocks/unblocks the NMDAR ion channel with rapid kinetics and high voltage dependency [62]. These properties are thought to underlie the apparent ability of memantine to allow normal physiological function of the receptor while impairing pathological activation. Blocking NMDARs has also been reported to mitigate Aβ-induced degeneration of cholinergic neurons in the rat magnocellular nuclear basalis and in rat hippocampal neurons [63–65]. Preclinical data suggest that NMDAR-mediated excitotoxicity may be linked to the effects of abnormal Aβ deposition in AD. More recently, memantine has been found to lower levels of secreted APP and Aβ peptide levels in neuronal cultures and in APP-Swe+PS1 AD transgenic mice [66, 67]. This is important as Aβ accumulation is the precipitating event in AD that leads to synaptic loss among other pathological features. Aβ is known to alter neuronal structure by mechanisms that involve the NMDARand inhibition of the NMDAR can reduce the toxic effects of Aβ.

As a currently approved drug, memantine is indicated for the symptomatic treatment of moderate to severe AD, and has been associated with a moderate decrease in clinical deterioration in AD [68]. Its usefulness has been proved in several clinical trials in which it has shown little but statistically significant improvements [69–72], also assessed by brain imaging [73]. Several systematic reviews of randomized controlled trials have established that memantine has small but helpful actions on cognition, mood, behavior, and the ability to perform daily activities in moderate to severe AD [74–76] nevertheless, the action of the drug in mild to moderate AD remains largely unknown. Importantly, memantine appears capable of achieving its pharmacological actions in a clinically well-tolerated manner and does not show the adverse effects typically associated with high-affinity NMDA-blockers. In trials reporting adverse effects, the primary memantine-induced adverse actions found were infrequent and comparable to placebo such as dizziness, occasional restlessness/agitation, constipation, ocular effects (cataracts, conjunctivitis), nausea, dyspnea, confusion, headache, fatigue, rash, diarrhea and urinary incontinence [77, 78]. On the basis of successful clinical trials, the use of memantine in the modulation of glutamatergic function may therefore represent a useful strategy for the treatment of AD. Furthermore, in vitro and clinical data indicate no adverse interactions between the approved cholinesterase inhibitors and memantine [79, 80].

Because memantine has exhibited efficacy and safety in placebo-controlled trials in patients with moderate to severe AD, the combination of memantine and various cholinesterase inhibitors appears well tolerated and they seem act synergistically due to their distinct mechanisms of action [81–85].

At present, a series of second generation memantine derivatives are currently in development and may have even greater neuroprotective properties than memantine [9, 86]. Whether and how these drugs translate to clinical medicine are awaited with interest.

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MEMANTINE TREATMENT FOR VASCULAR DEMENTIA

Memantine has also been described as effective and well tolerated for the treatment of mild to moderate VD in several randomized clinical trials [87–89]. VD ranks second in preval‎ence as a form of dementia after AD [1], and they often co-exist. It is not infrequent that confusion can occur between both disorders, due to the similarity of their clinical symptoms. VD is a degenerative cerebrovascular disease that leads to a progressive decline in memory and cognitive functioning. The root of this issue relates to a chronic reduced cerebral blood flow (vascular insufficiency) carrying oxygen and nutrients to the brain that may be impaired by a strategic infarct (ischemia) or small (silent) multi-infarcts, hemorrhagic cerebrovascular disease, or can derive from small vessel disease (including lacunar lesions and Binswanger’s disease) [90]. Apart from acute ischemia from embolic or atherothrombotic large vessels occlusion, ischemic-hypoxic brain lesions also can be originated by cardiovascular diseases, such as hypertension or diabetes, which cause a narrowing of the lumen of small vessels [91]. In addition, senile arteriolosclerosis produces tortuosity and elongation of arterioles [92].

Since it may be partly preventable, VD needs to be differentiated from other causes of dementia such as AD, Lewy body-type dementia and PD. Special attention has to be given when attempting to make a differential diagnosis, to the following steps that may lead to a diagnosis of VD [93]:

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Oxygen and glucose deprivation are followed by an elevation of extracellular glutamate both in ischemic brain damage and traumatic brain injury [50] that results in consequent NMDR overactivation and massive Ca2+ influx. Failure of astrocyte functions also has been reported [94] such as maintenance of blood-brain barrier (BBB) cells in cerebral microvasculature and endothelial permeability [95]. Disruption of tight junctions among endothelial cells, degradation of the basal lamina and extracellular matrix by metalloproteinases-2 and −9 are involved in BBB breakdown and cerebral hemorrhagia [96–98]. In addition, adhesion and transmigration of leukocyte occurs, leading to activation of an inflammatory response [99]. For a review of downstream processes after calcium entry in ischemia, see Ref. [48].

In general, cerebral lesions after ischemic injury begin with an initial reversible stage where neurons finally become necrotic [100]. The cells of the ischemic core undergo anoxic depolarizations that expand to the penumbral region and a lack of energy that leads to necrosis [101]. Since the ischemic area grows as the number of peri-infarct depolarizations increases, the extension of severe damaged area can be attenuated by blocking NMDAR-mediated depolarizations [102].

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PARKINSON’S DISEASE PATHOGENESIS, NMDARS, GLUTAMATERGIC TRANSMISSION AND MEMANTINE TREATMENT

Parkinson’s Disease Pathology, NMDARs and Glutamatergic Transmission

PD is the second most frequent progressive-type neurodegenerative disorder after AD [103] and represents, like AD, a large health burden to society. Approximately 1% of the population over 60 years of age is affected [104]. Classical clinical symptoms include tremors; bradykinesia, or slowness of movement; and rigidity, or akinesia.

The primary underlying pathology of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) that innervates the striatum. At post-mortem examination, the depletion frequently exceeds 90% [105] with consequent loss of neuronal systems responsible for motor functions. Besides, cell death is not limited to dopaminergic neurons in SNpc and can expand to other areas of the brain, leading to extensive neuronal death. It is not infrequent to find dementia in patients afflicted by PD. A further archetypal hallmark is the formation of intracytoplasmic inclusions, termed Lewy bodies, in remaining neurons [106].

To date, no curative treatment for PD exists but symptomic control can be achieved. The most effective treatments are based on the replacement of dopamine (DA) loss using either the precursor of DA, L-dihydroxyphenylalanine (L-dopa), or agonist-mediated stimulators of DA receptors, epitomized by pramipexole or ropinirole. Essentially, all patients require L-dopa at some stage of disease progression, in spite of its adverse effects, such as the “wearing-off” phenomenon – relating to the shortening of sustainable pharmacological activity [107] as occurs when the symptoms of PD, attenuated by the treatment, become more intense prior to the next expected dose. Albeit that L-dopa is associated with dyskinesia or diminished voluntary movements and the presence of involuntary movements, it must be recognized that, since L-dopa’s clinical introduction, survival with PD has been considerably prolonged [108].

NMDARs are very abundant in the striatum [109], comprised by putamen and caudate nucleus, where they regulate the release of neurotransmitters like γ-aminobutyric acid (GABA) and ACh [110]. NMDARs downstream of the striatum also participate in modulating the activities of basal ganglia circuit and are present in the subthalamic nucleus (STN), globus pallidus internus (GPi) [111], and cerebral cortex [112]. The activity of NMDARs is largely regulated by dopaminergic afferents. D1 receptor agonists elicit a fast enhancement of NMDA-induced depolarization of striatal cells, whereas D2 receptor agonists attenuate this [113].

Execution of voluntary movement starts with the cortex (executive) signaling the caudate and putamen via glutamatergic projections or from the SNpc via dopamine. The Striatum then sends inhibitory GABAergic signals to GPi leads to disinhibition of the thalamic ventral anterior (VA). This leads to stimulatory signaling of the motor cortex by the thalamic VA and initiation of movement. As described, PD is characterized by depletion of dopaminergic neurons, leading to a disinhibition of striatal neurons that have inhibitory D2 dopaminergic receptors and project to the globus pallidus externus (GPe), and to a decrease of striatal neuron activity projecting to the GPi and the substantia nigra pars reticulata (SNpr) that have D1 excitatory dopaminergic receptors [114]. All these striatal efferent pathways are mediated by GABA and are inhibitory so that GPe projection to the STN (also inhibitory) is reduced. Therefore, the suppression of dopaminergic modulation disinhibits STN neurons, rendering them overactive [115]. The enhanced activity of excitatory glutamatergic STN projections to GPi and SNpr (besides lack of inhibitory input from the GPe stated above) further enhance the activity of their GABAergic neurons [116]. Spontaneous movement is reduced by inhibiting the activity of thalamic glutamatergic and excitatory VA projections VA to the motor frontal cortex (see Fig. 4A and B). Acetylcholinergic neurons in the brainstem and basal forebrain areas, are regulated by prefrontal cortex glutamatergic projections, and seem to be of special relevance in modulating motor, emotional and mnemonic functions [117], therefore a decrease of thalamocortical input entails a deficit of ACh, leading to a decline in voluntary movements. Likewise, the striatum and SNpc can receive glutamatergic excitatory input from the neocortex [118].

Fig. (4)

Classical model of normal activity of the basal ganglia and malfunctioning in PD (reviewed in Ref. [114]). Thin arrows indicate downregulation and thick arrows upregulation. Blue arrows show glutamatergic activatory efferents, red arrows indicate inhibitory GABAergic efferents and green arrows, activatory/inhibitory projections. (A) The ‘direct pathway’ is comprised of striatal neurons with D1 activatory dopaminergic receptors and their GABAergic efferent projections to the globus pallidus internus (GPi) which together the SNpr transmit inhibitory signals via GABAergic output to the thalamic ventral anterior (VA) nucleus. The ‘indirect pathway’ is comprised of striatal neurons with D2 inhibitory dopaminergic receptors. The striatum (composed of caudate and putamen) projects GABAergic output to the globus pallidus externus (GPe). From this point, they synapse to the nucleus subthalamicus (STN), from which glutamatergic activatory projections reach the GPi and the substantia nigra (SNpc/SNpr). The subthalamic nucleus also gets excitatory input directly from the cortex and induces the GPi to increase GABA release in the VA. While GPe keeps it in check, the SNpc dopamine binds D2 receptors to inhibit this pathway, blocking the inhibition of the subthalamic circuit by GPe. Additionally, the striatum and the SNpc receive glutamatergic efferents from the neocortex.

(B) Loss of dopaminergic afferents (broken green arrows) entails a dis-repression of striatal D2 neurons leads to over-activity of their GABAergic projections to the GPe, and this in turn decreases its GABAergic efferent activity to the STN. As a consequence, STN glutamatergic projections to the GPi render over-active, increasing GABAergic output from the GPi to the VA. On the contrary, the D1 striatal neurons are underactive, therefore the GABAergic output to the GPi and to the SNpr are reduced and consequently the GABAergic output from both to the VA is increased. As a consequence in both cases, the loss of dopaminergic projections causes a failure to desinhibit the thalamocortical output, leading to bradykinesia, a typical symptom in PD. (C) (D) Possible targets at the basal ganglia level of NMDAR antagonists amantadine and memantine. Broken arrows mean suppression of output projections. A putative target is the STN (C), overactive in PD by blocking the subthalamic stimulation of GPi and a normalization of downstream thalamocortical connections. Other target could be the indirect pathway from the striatum (D), triggering a dis-repression of SNpr and leading to a normalization of STN activity and therefore a thalamic-cortical neuron well-functioning.

Accordingly, increased activity of STN neurons has been described in monkeys treated with 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine (MPTP), a neurotoxin that induces parkinsonism in animal models [119], and NMDAR antagonists have been reported to provide potent neuroprotective action [120]. NMDARs localized to the STN also play a role in sustaining pathological hyperactivity observed in a 6-hydroxydopamine rat model of parkinsonism, and the infusion of a NMDAR antagonist into the STN normalized the activity of the basal ganglia [121].

NMDARs are also found on dopaminergic neurons in the SNpc [122]. Increased glutamatergic input to dopaminergic neurons through NMDARs might accelerate the degenerative process [118]. It has been reported that NMDAR antagonists elevate striatal DA release in vivo [123–125] and, given this, would likely be beneficial in PD. In testing this conjecture, the initial class of selective antagonists’ studies in parkinsonism were the phenylethanolamines. One of them, ifenprodil, shows anti-parkinsonian activity in reserpine-treated rats and MPTP-treated monkeys [126].

The effect of an anti-PD medication can be enhanced by NMDAR antagonists. In animal models of PD, NMDAR antagonists have shown a potentiation of the anti-parkinsonian effect of L-dopa and locomotion [109]. Some anticholinergic drugs are also non-competitive antagonists of the NMDAR and, at therapeutic concentrations, may interact with NMDARs and palliate PD [127]. Just as anticholinergics are able to work as NMDA antagonists, NMDA antagonists also can function as anticholinergic agents [128] and normalize the glutamatergic control of corticostriatal ACh release. In the striatum, NMDA stimulation enhances the release of ACh, and antagonists can effectively inhibit this release [110].

Since oxidative products of DA play a role in dopaminergic cell death [129], the use of NMDA antagonists could additionally allow for a decrease in L-dopa dosage and, thereby, diminish any potential oxidative damage. Other NMDA antagonists, such as dextromethorphan, have been reported to suppress dyskinesia in PD patients, but adverse effects (primarily drowsiness) at higher doses would likely limit such a treatment strategy [130]. On the other hand, amantadine (1-amino adamantine) a non-selective NMDA antagonist used to treat PD, provides mild L-dopa-induced anti-dyskinetic benefit with a moderate degree of NMDA antagonist activity [131]. Furthermore, in a large retrospective study, amantadine was associated with an increased lifespan in patients with PD, suggesting that it may have neuroprotective properties [132].

Memantine Treatment for Parkinson’s Disease

Given that memantine carries out its therapeutic action by targeting the glutamatergic transmission, and the role of NMDARs in basal ganglia for the development of PD symptoms, memantine has also been tested in parkinsonian patients with a degree of moderate success.

Although memantine’s chemical structure is related to amantadine’s, and they act in a somewhat similar pharmacological fashion, memantine does not appear to share the anti-dyskinetic activity of amantadine [133]. However, like DA agonists and other NMDA antagonists, memantine is able to reverse neuroleptic-induced catalepsy [134].

Using patch-clamp techniques, it has been reported that memantine blocks the NMDA ion channel [135], binds to the MK-801 binding site of the NMDAR [136], and decreases NMDA-induced membrane currents. The mechanism of action postulated is a normalization of the corticostriatal glutamatergic activity and/or the subthalamopallidal pathways that are overactive in PD (see Fig. 4C and D). Contrasting with amantadine, in which anti-dyskinetic activity could be rationalized by blocking subthalamic activity, the anti-parkinsonian and synergistic effect of memantine could be due to the inhibition of glutamatergic transmission in the striatum, whereby striatonigral neurons are GABAergic and inhibitory, causing a decreased inhibition of nigrostriatal dopaminergic neurons in SNpc and thereby an elevation in DA release [137].

To investigate the primary efficacy of memantine, a double-blind crossover exploratory trial was designed [133], in which 12 patients with idiopathic PD were randomized to memantine or placebo during two weeks in an escalated dosage from 10 mg/day to 30 mg/day at day 7, and after this time, a single dose of L-dopa was administrated to each arm. Five patients were taking concomitant PD medication (but not amantadine). As expected, a clear anti-parkinsonian activity was observed in terms of counteracting bradykinesia and resting tremor. A synergistic enhancement of L-dopa and memantine seemed evident with motor function. Side effects, mainly drowsiness and nausea, occurred with a similar frequency in both groups.

To further assess the efficacy of memantine, a randomized controlled study was performed with patients suffering from dementia with Lewy bodies or PD dementia that resulted in an improvement in the majority of variables stated in the clinical global impression of change test for the memantine group compared to placebo [138, 139] and a better response assessed in other useful rating scales [140], while the proportion of adverse events was similar to placebo and improved L-dopa-related dyskinesia and the “off” effect [141].

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CONCLUDING REMARKS

Several studies show how memantine positively impacts cognition and, hence, they lend credence to the hypothesis that neurotoxicity of glutamatergic overstimulation is involved in dementia. The neuroprotective properties of memantine have also been demonstrated in several in vitro experimental settings, albeit further studies are needed to examine whether memantine treatment and cholinergic treatments could ultimately prove to be complementary or even synergistic. Memantine has also shown efficacy in PD, revealing itself as a potentially promising new therapeutic option. Importantly, as memantine treatment is generally well tolerated, combining it with other therapies is a valuable and feasible option both with AD and PD. However, although memantine was approved for treating mild to moderate AD, its results are modest; therefore, a second generation of adamantane-based drugs are being designed in the hope of improving its clinical efficacy. In conclusion, given the wealth of data on NMDAR activity in AD, VD, and PD, memantine and other drugs that emerge in the NMDAR antagonist class are likely to have an increasingly significant role to play in the future treatment of these diseases.

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Acknowledgments

This work was supported in part by Radiology Department of Brigham and Women’s Hospital (BWH) and the Intramural Research Program, National Institute on Aging (NIA). Jack T. Rogers is a recipient of Zenith Fellows award of Alzheimer’s Association. We want to thank Ms. Kim Lawson at BWH Radiology Department for her editing of our manuscript. This work was also supported by Grants from Alzheimer’s Association and NIH to DKL.

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LIST OF ABBREVATIONS

Ach	Acetylcholine
AD	Alzheimer’s disease
ADDLs	Aβ-derived diffusible ligands
Amantadine	1-Amino adamantine
AMPA	α-Amino 3-hydroxy 5-methyl 4-isoxazolepropionic acid
APP	Amyloid precursor protein
Aβ	Beta amyloid peptide
BBB	Blood-brain barrier
CNS	Central nervous system
DA	Dopamine
FAD	Familial Alzheimer’s disease
GABA	γ-Aminobutyric acid
GPe	Globus pallidus externus
GPi	Globus pallidus internus
L-dopa	L-dihydroxyphenylalanine
LTP	Long-term potentiation
Memantine	1-Amino-3,5-dimethyladamantane
MPTP	1-Methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine
NFTs	Neurofibrillary tangles
NMDA	N-Methyl D-Aspartate
NOS and NO	Nitric oxide synthase and nitric oxide
PCP	Phencyclidine
PD	Parkinson’s disease
PS1 and PS2	Presenilin-1 and Presenilin-2 protein
SNpc	Substantia nigra pars compacta
SNpr	Substantia nigra pars reticulate
STN	Subthalamic nucleus
VD	Vascular dementia

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Footnotes

CONFLICT OF INTEREST

The authors declare that they do not have any conflicts of interest.

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