녹내장 실명을 막기 위한 비타민, 미네랄, 한약재 탐구 논문...

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Curr Neuropharmacol. 2018 Aug; 16(7): 1004–1017.

Published online 2018 Aug. doi: 10.2174/1570159X15666171109124520

PMCID: PMC6120110

PMID: 29119928

Rational Basis for Nutraceuticals in the Treatment of Glaucoma

Morrone Luigi Antonio,1,* Rombolà Laura,1 Adornetto Annagrazia,1 Corasaniti Maria Tiziana,2 and Russo Rossella1

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Abstract

Background:

Glaucoma, the second leading cause of blindness worldwide, is a chronic optic neuropathy characterized by progressive retinal ganglion cell (RGC) axons degeneration and death.

Primary open-angle glaucoma (OAG), the most common type, is often associated with increased intraocular pressure (IOP), however other factors have been recognized to partecipate to the patogenesis of the optic neuropathy. IOP-independent mechanisms that contribute to the glaucoma-related neurodegeneration include oxidative stress, excitotoxicity, neuroinflammation, and impaired ocular blood flow. The involvement of several and diverse factors is one of the reasons for the progression of glaucoma observed even under efficient IOP control with the currently available drugs.

Methods:

Current research and online content related to the potential of nutritional supplements for limiting retinal damage and improving RGC survival is reviewed.

Conclusion:

Results: Recent studies have suggested a link between dietary factors and glaucoma risk. Particularly, some nutrients have proven capable of lowering IOP, increase circulation to the optic nerve, modulate excitotoxicity and promote RGC survival. However, the lack of clinical trials limit their current therapeutic use. The appropriate use of nutraceuticals that may be able to modify the risk of glaucoma may provide insight into glaucoma pathogenesis and decrease the need for, and therefore the side effects from, conventional therapies.

Conclusion:

The effects of nutrients with anti-oxidant and neuroprotective properties are of great interest and nutraceuticals may offer some therapeutic potential although a further rigorous eval‎uation of nutraceuticals in the treatment of glaucoma is needed to determine their safety and efficacy.

전 세계적으로 실명의 두 번째 주요 원인인 녹내장은 진행성 망막 신경절 세포(RGC) 축삭 변성 및 사멸을 특징으로 하는 만성 시신경 병증입니다.

가장 흔한 유형인 원발성 개방각 녹내장(OAG)은

안압 상승과 관련이 있는 경우가 많지만,

시신경 병증의 발병에는 다른 요인도 관여하는 것으로 알려져 있습니다.

녹내장 관련 신경 퇴행에 기여하는 안압과 무관한 메커니즘에는

산화 스트레스,

흥분 독성,

신경 염증,

안구 혈류 장애 등이 있습니다.

여러 가지 다양한 요인이 관여하는 것은 현재 사용 가능한 약물로 안압을 효율적으로 조절해도 녹내장이 진행되는 이유 중 하나입니다.



방법:

망막 손상을 제한하고 RGC 생존을 개선하기 위한 영양 보충제의 잠재력과 관련된 최신 연구 및 온라인 콘텐츠를 검토합니다.



결론:

결과: 최근 연구에 따르면 

식이 요인과 녹내장 위험 사이에 연관성이 있는 것으로 나타났습니다. 

특히 일부 영양소는 안압을 낮추고 

시신경 순환을 증가시키며 

흥분성 독성을 조절하고 

RGC 생존을 촉진할 수 있는 것으로 입증되었습니다. 

그러나 임상시험이 부족하여 현재 치료제로 사용하는 데는 한계가 있습니다. 녹내장 위험을 조절할 수 있는 건강기능식품을 적절히 사용하면 녹내장 발병 기전에 대한 통찰력을 제공하고 기존 치료법의 필요성과 부작용을 줄일 수 있습니다.



결론:

항산화 및 신경 보호 특성을 가진 영양소의 효과는 큰 관심을 끌고 있으며, 

녹내장 치료에서 기능식품의 안전성과 효능을 결정하기 위해서는 

기능식품에 대한 보다 엄격한 평가가 필요하지만 기능식품이 치료 잠재력을 제공할 수 있습니다.

Keywords: Glaucoma, retinal ganglion cells, neurodegeneration, oxidative stress, nutraceuticals, neuroprotection

1. Introduction

Glaucoma is a neurodegenerative disease characterized by retinal ganglion cells (RGC) death, typical visual field defect and eventual blindness [1]. Elevated intraocular pressure (IOP), aging, genetic, epigenetic and environmental factors are among a number of recognized risk factors for glaucoma [2, 3]. Glaucoma is thus a progressive optic neuropathy with complex pathophysiology and RGC loss in glaucoma remains incompletely understood [4]. Several mechanisms have been suggested to play a role in RCG damage including oxidative stress, excitotoxicity and neuroinflammation [5-7]. Particularly, excitotoxicity through the overactivation of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors [8, 9] has been proposed as one of the determinants involved in RGC damage [5]. Furthermore, several studies demonstrate that mitochondrial perturbations are among the very first changes occurring within RGCs during glaucoma [7, 10-12] suggesting that oxidative stress is also a key mechanism of excitotoxic, glutamate induced RGC loss [8, 13, 14]. Several studies have shown that free radical species can cause RGC death by inhibition of key enzymes of the tricarboxylic acid cycle, the mitochondrial electron transport chain, and mitochondrial calcium homeostasis, leading to defective energy metabolism [15, 16]. Interestingly, increased levels of oxidative stress markers were observed in aqueous humor of patients with primary open-angle glaucoma (POAG) [17, 18] and with primary angle closure glaucoma (PACG) [19]. Accordingly, a recent meta-analysis by Benoist d’Azy and Colleagues reported that oxidative stress increased in glaucoma patients, both in serum and aqueous humor [20]. In addition to its detrimental effect on the optic nerve, oxidative stress has also been suggested to damage the trabecular meshwork (TM) [21-23] resulting in an increase in the IOP. Incidentally, recent experimental data revealed that autophagy modulation occurs in RGC under glaucoma-related stressing conditions supporting the hypothesis that dysfunctional autophagy might participate to the process leading to RGC death [24]. Despite accumulating evidence of pressure-independent causes of glaucomatous optic neuropathy has led to the recognition that lowering IOP alone may often be insufficient for the long-term preservation of visual function [25], most of the current treatment modalities are based on lowering the IOP and a need exists for novel therapies able to save RGCs from injury or to repair damaged neurons. Interestingly, several studies have suggested a link between dietary factors, now named “nutraceuticals” [26, 27] and glaucoma risk [28, 29]. Deficiencies of specific nutrients have been found in patients with glaucoma and supplementation may play a role in treatment [28]. Interestingly, some nutraceuticals have shown their ability to lower IOP [30-32], increase circulation to the optic nerve [28], modulate excitotoxicity and promote RGC survival [14, 33-36]. In this respect, a prospective study for ten years revealed an association between low intake of antioxidant nutrients and a higher risk of open angle glaucoma [37]. On the contrary, Kang and Colleagues reported no strong associations between antioxidants intake and primary open-angle glaucoma (OAG) risk [38]. Likewise, more recently, a two-year follow-up of oral antioxidants supplementation in OAG did not demonstrate beneficial short-term effects [39]. This apparent discrepancy could be explained by considering the sample size estimate and the different features of clinical trials. In fact, although some nutraceuticals have been described as neuroprotective, the lack of clinical trials examining their benefits for glaucoma limits their current therapeutic use [1, 40] suggesting that well designed clinical trials are needed to assess their efficacy and tolerability in glaucoma treatment. Therefore, appropriate use of nutraceuticals with anti-oxidant and neuroprotective properties may be able to modify the risk of glaucoma, provide insight into glaucoma pathogenesis and decrease the need for, and therefore the side effects from, conventional therapies.

This review discusses the most current knowledge on the neuroprotective effects of a number of nutraceuticals in RGC damage and their potential benefit in glaucoma treatment.

녹내장은 

망막 신경절 세포(RGC)의 사멸, 전형적인 시야 결손 및 

최종 실명을 특징으로 하는 

신경 퇴행성 질환입니다[1]. 

안압 상승, 노화, 유전적, 후성유전적, 환경적 요인이 

녹내장의 여러 위험 요인으로 알려져 있습니다[2, 3]. 

따라서 

녹내장은 

복잡한 병리 생리를 가진 진행성 시신경 병증이며 

녹내장에서의 RGC 손실은 아직 불완전하게 이해되고 있습니다 [4]. 

산화 스트레스, 

흥분성 독성 및 신경 염증을 포함한 여러 가지 메커니즘이 

RGC 손상에 관여하는 것으로 제안되었습니다 [5-7]. 

특히 

N-메틸-D-아스파르트산염(NMDA) 및 비-NMDA 글루타메이트 수용체[8, 9]의 과활성화를 통한 흥분 독성이 

RGC 손상과 관련된 결정 요인 중 하나로 제안되었습니다[5]. 

또한, 

여러 연구에 따르면 미토콘드리아 교란은 

녹내장 발생 시 RGC 내에서 가장 먼저 발생하는 변화 중 하나이며[7, 10-12], 

산화 스트레스가 흥분성 글루타메이트에 의한 RGC 손실의 핵심 메커니즘임을 시사합니다[8, 13, 14]. 

여러 연구에 따르면 

자유 라디칼 종은 트리카르복실산 순환의 주요 효소, 

미토콘드리아 전자 수송 사슬 및 미토콘드리아 칼슘 항상성을 억제하여 

에너지 대사에 결함을 일으켜 RGC 사멸을 유발할 수 있습니다 [15, 16]. 

흥미롭게도 

원발 개방각 녹내장(POAG) [17, 18] 및 원발 폐쇄각 녹내장(PACG) [19] 환자의 방수에서 

산화 스트레스 마커의 증가 수준이 관찰되었습니다. 

따라서 

최근 Benoist d'Azy와 동료들의 메타 분석에 따르면 

녹내장 환자에서 혈청과 방수 모두에서 산화 스트레스가 증가했다고 보고했습니다 [20]. 

산화 스트레스는 

시신경에 해로운 영향을 미칠 뿐만 아니라 

섬유주 그물망(TM)을 손상시켜[21-23] 안압을 증가시키는 것으로 알려져 있습니다. 

또한, 

최근 실험 데이터에 따르면 

녹내장 관련 스트레스 조건에서 RGC에서 자가포식 조절이 일어나는 것으로 밝혀져 

기능 장애 자가포식이 

RGC 사멸로 이어지는 과정에 관여할 수 있다는 가설을 뒷받침합니다 [24]. 

녹내장성 시신경병증의 압력 독립적 원인에 대한 증거가 축적되면서 

안압을 낮추는 것만으로는 시각 기능을 장기적으로 보존하는 데 불충분할 수 있다는 인식이 확산되고 있지만[25], 

현재 대부분의 치료 방식은 

안압을 낮추는 데 기반을 두고 있으며 

RGC를 손상으로부터 보호하거나 손상된 뉴런을 복구할 수 있는 새로운 치료법이 필요한 실정입니다. 

흥미롭게도 

여러 연구에서 현재 "건강기능식품"[26, 27]으로 명명된 식이 요인과 녹내장 위험 사이의 연관성을 제시했습니다[28, 29]. 

녹내장 환자에서 

특정 영양소의 결핍이 발견되었으며 

보충제가 치료에 중요한 역할을 할 수 있습니다 [28]. 

흥미롭게도 

일부 건강기능식품은 안압을 낮추고[30-32], 

시신경 순환을 증가시키며[28], 

흥분 독성을 조절하고 

RGC 생존을 촉진하는 능력을 보여주었습니다[14, 33-36]. 

이와 관련하여 10년간의 전향적 연구에 따르면 항산화 영양소 섭취 부족과 개방각 녹내장 위험 증가 사이의 연관성이 밝혀졌습니다 [37]. 반대로 Kang과 동료들은 항산화제 섭취와 원발성 개방각 녹내장(OAG) 위험 사이에 강력한 연관성이 없다고 보고했습니다 [38]. 마찬가지로, 최근에는 OAG에서 경구 항산화제 보충제를 2년간 추적 관찰한 결과 단기적으로 유익한 효과가 입증되지 않았습니다 [39]. 이러한 명백한 불일치는 표본 크기 추정치와 임상시험의 다양한 특징을 고려하면 설명할 수 있습니다. 

실제로 

일부 건강기능식품은 신경 보호 효과가 있는 것으로 알려져 있지만, 

녹내장에 대한 효능을 조사한 임상시험이 부족하여 

현재 치료제로의 사용이 제한되어 있어[1, 40] 

녹내장 치료에서 효능과 내약성을 평가하기 위해서는 잘 설계된 임상시험이 필요합니다. 

따라서 항산화 및 신경 보호 특성을 가진 건강기능식품을 적절히 사용하면 녹내장 위험을 조절하고 녹내장 발병 기전에 대한 통찰력을 제공하며 기존 치료법의 필요성과 그에 따른 부작용을 줄일 수 있습니다.

이 리뷰에서는 RGC 손상에 대한 여러 건강기능식품의 신경 보호 효과와 녹내장 치료에서의 잠재적 이점에 대한 최신 지식을 논의합니다.

2. Vitamins

Considering the key role played by oxidative stress in RGC damage, antioxidant vitamins have been suggested as potential neuroprotective agents [41, 42]. However, although their deficiency may be linked to symptoms of optic-nerve dysfunction, the association between serum vitamin levels and glaucoma preval‎ence in humans remains controversial. For example, in 2003, the Nurses’ Health Study and Health Professionals Follow-up Study reported no strong association between the risk of primary open-angle glaucoma and vitamin C, vitamin E, and vitamin A consumption [38]. Accordingly, a recent meta-analysis by Li and Colleagues reported that normal-tension glaucoma (NTG) risk is not associated with serum vitamin B6, vitamin B12, or folic acid levels [43]. Moreover, another meta-analysis reported no association between serum vitamin B6, vitamin B12, or vitamin D levels and the different types of glaucoma [44]. On the contrary, the Rotterdam Study, a prospective study on a glaucoma cohort of 3500 Individuals, revealed an association between low intake of antioxidant nutrients, including retinol equivalents and vitamin B1, and a higher risk of open angle glaucoma [37]. Yuki and Colleagues investigated the levels of antioxidants as vitamins A, C, E, folic acid in the serum of Japanese patients with normal-tension glaucoma compared with normal controls. Interestingly, they found lower serum levels of vitamin C in glaucoma patients [45]. Furthermore, Asregadoo reported a statistically significant lower thiamine blood level in 38 glaucoma patients than in 12 controls [46]. Moreover, Turgut and Colleagues reported that plasma levels of vitamin B6 increase in NTG or POAG patients [47]. Conversely no statistical differences were observed in serum vitamin B12 and folate levels among control subjects and glaucoma groups. In addition, the plasma level of homocysteine was found to be increased only in patients with pseudoexfoliative glaucoma (PXG) [47]. Similar results were observed by Cumurcu and Colleagues [48] and Xu and Colleagues [49]. Moreove, Kang and Colleagues investigated the association between B vitamins (folate, vitamin B6, and vitamin B12) intake and exfoliation glaucoma (EG) or suspected EG (SEG) risk and reported that higher folate, but not vitamin B6 and vitamin B12 intake, was associated with a lower risk for EG/SEG [50]. Wang and Colleagues also investigated, in a cross-sectional study included 2912 participants, the potential association between glaucoma preval‎ence and supplemental intake, as well as serum levels of vitamins A, C and E. The authors reported no association between vitamins with glaucoma preval‎ence, however supplementary consumption of vitamin C was found to be associated with decreased odds of glaucoma [51]. Interestingly, Xu and Colleagues reported tha vitamin C shows a dose-dependent effect against oxidative insult by modulation of iron homeostasis and intracellular ROS formation and, in addition, elicits the activation of the autophagic lysosomal pathway in TM cells [52]. Moreover, Lee and Colleagues reported a correlation of aqueous humor ascorbate concentration with intraocular pressure as well as outflow facility in hereditary buphthalmic rabbits [53] but found no correlation in OAG patients [54]. Vitamin C has also been found, in vitro, to stimulate synthesis of hyaluronic acid in trabecular meshwork from glaucomatous eyes [55] and to reduce the viscosity of hyaluronic acid and increase outflow through the trabeculum [56]. More recently, Goncalves and Colleagues reported vitamin D insufficiency is associated with POAG [57]. Interestingly, topical administration of 1α,25-dihydroxyvitamin D(3) or its analog, 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D(3) (2MD), markedly reduced IOP in non-human primates [58]. However, Krefting and Colleagues reported that the administration of vitamin D3 to healty volunteers with low levels of 25(OH)D does not affect IOP [59]. In 2010, Ko and Colleagues reported that vitamin E deficiency increased RGC loss in a rat model of glaucoma [60]. Particularly, the Authors found that vitamin E deficiency alone for ten weeks did not increase RGC death. However, when vitamin E deficiency was combined with IOP elevation for five weeks, there was a significant increase in RGC death and higher levels of retinal lipid peroxidation. Interestingly, vitamin E deficiency did not change the activities of superoxide dismutase (SOD) and catalase in the rat retina after IOP elevation [60]. Moreover, Yu and Colleagues demonstrated that vitamin E is able to reduce the transforming growth factor-beta2 (TGFb2)-induced cellular changes in cultured human trabecular meshwork cells, suggesting that increasing the antioxidative capacity may help to lower the incidence of characteristic glaucomatous changes in TM [61]. Interestingly, more recently, Williams and Colleagues, demonstrated that oral administration of vitamin B3 (nicotinamide) a precursor of nicotinamide adenine dinucleotide (NAD) or Nmnat1(nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1) gene therapy reduces mitochondrial vulnerability and prevents glaucoma in aged mice [11].

RGC 손상에서 산화 스트레스의 주요 역할을 고려할 때, 

항산화 비타민은 잠재적인 신경 보호제로 제안되었습니다 [41, 42]. 

그러나 

비타민 결핍이 시신경 기능 장애 증상과 관련이 있을 수 있지만, 

인간의 혈청 비타민 수치와 녹내장 유병률 사이의 연관성은 여전히 논란의 여지가 있습니다. 

예를 들어, 2003년 간호사 건강 연구 및 보건 전문가 추적 연구에서는 원발성 개방각 녹내장의 위험과 비타민 C, 비타민 E, 비타민 A 섭취 사이에 큰 연관성이 없다고 보고했습니다[38]. 따라서 Li와 동료들의 최근 메타분석에서는 정상안압녹내장(NTG) 위험은 혈청 비타민 B6, 비타민 B12 또는 엽산 수치와 관련이 없다고 보고했습니다[43]. 또한 또 다른 메타 분석에서는 혈청 비타민 B6, 비타민 B12 또는 비타민 D 수치와 녹내장의 다른 유형 사이에 연관성이 없다고 보고했습니다 [44]. 

반대로 3500명의 녹내장 코호트를 대상으로 한 전향적 연구인 로테르담 연구에서는 

레티놀 등가물과 비타민 B1을 포함한 항산화 영양소의 낮은 섭취와 

개방각 녹내장의 높은 위험 사이의 연관성이 밝혀졌습니다 [37]. 

Yuki와 동료들은 정상안압 녹내장을 가진 일본 환자의 혈청에서

 비타민 A, C, E, 엽산과 같은 항산화제의 수치를 정상 대조군과 비교하여 조사했습니다. 

흥미롭게도 녹내장 환자에서 혈청 내 비타민 C 수치가 낮다는 사실을 발견했습니다[45]. 

또한 아스가두는 38명의 녹내장 환자에서 12명의 대조군보다 통계적으로 유의미하게 낮은 티아민 혈중 농도를 보고했습니다 [46]. 또한 Turgut과 동료들은 NTG 또는 POAG 환자에서 비타민 B6의 혈장 수치가 증가한다고 보고했습니다 [47]. 

반대로 대조군과 녹내장 그룹 간의 혈청 비타민 B12 및 엽산 수치에는 통계적 차이가 관찰되지 않았습니다. 또한 호모시스테인의 혈장 수준은 가성 각질 녹내장(PXG) 환자에서만 증가하는 것으로 밝혀졌습니다 [47]. 비슷한 결과가 Cumurcu와 동료들 [48] 및 Xu와 동료들 [49]에 의해 관찰되었습니다. 또한 Kang과 동료들은 비타민 B군(엽산, 비타민 B6, 비타민 B12) 섭취와 각질 녹내장(EG) 또는 의심되는 EG(SEG) 위험 사이의 연관성을 조사한 결과 비타민 B6와 비타민 B12 섭취가 아닌 엽산 섭취가 높을수록 EG/SEG 위험이 낮아진다고 보고했습니다 [50]. 

Wang과 동료들은 또한 2912명의 참가자를 대상으로 한 횡단면 연구에서 녹내장 유병률과 보충제 섭취, 비타민 A, C, E의 혈청 수치 사이의 잠재적 연관성을 조사했습니다. 저자는 비타민과 녹내장 유병률 사이에 연관성이 없다고 보고했지만 비타민 C의 보충 섭취는 녹내장 발병률 감소와 관련이 있는 것으로 밝혀졌습니다 [51]. 흥미롭게도 Xu와 동료들은 비타민 C가 철 항상성 및 세포 내 ROS 형성을 조절하여 산화적 손상에 대한 용량 의존적 효과를 보이며, 또한 TM 세포에서 자가포식 리소좀 경로의 활성화를 유도한다고 보고했습니다 [52]. 또한 Lee와 동료들은 유전성 부프토마티스 토끼에서 안압 및 유출 시설과 방액 아스코르브산염 농도의 상관관계를 보고했지만[53], OAG 환자에서는 상관관계가 발견되지 않았습니다[54]. 

또한 비타민 C는 녹내장 눈의 섬유주 그물망에서 히알루론산의 합성을 자극하고[55], 히알루론산의 점도를 낮추고 섬유주를 통한 유출을 증가시키는 것으로 시험관 내에서 밝혀졌습니다[56]. 최근에는 Goncalves와 동료들이 비타민 D 결핍이 POAG와 관련이 있다고 보고했습니다 [57]. 흥미롭게도 1α,25-디하이드록시비타민 D(3) 또는 그 유사체인 2-methylene-19-nor-(20S)-1α,25-디하이드록시비타민 D(3)(2MD)의 국소 투여는 비인간 영장류의 안압을 현저하게 감소시켰습니다 [58]. 그러나 Krefting과 동료들은 25(OH)D 수치가 낮은 건강한 지원자에게 비타민 D3를 투여해도 IOP에 영향을 미치지 않는다고 보고했습니다 [59]. 2010년에 Ko와 동료들은 비타민 E 결핍이 녹내장 쥐 모델에서 RGC 손실을 증가시킨다고 보고했습니다 [60]. 특히 저자들은 10주 동안 비타민 E 결핍만으로는 RGC 사멸이 증가하지 않는다는 사실을 발견했습니다. 그러나 비타민 E 결핍과 안압 상승을 5주 동안 병용했을 때 RGC 사멸이 유의하게 증가하고 망막 지질 과산화 수치가 더 높아졌습니다. 

흥미롭게도 비타민 E 결핍은 안압 상승 후 쥐 망막에서 슈퍼옥사이드 디스뮤타제(SOD)와 카탈라아제의 활성을 변화시키지 않았습니다 [60]. 또한 Yu와 동료들은 비타민 E가 배양된 인간 섬유주망 세포에서 형질전환성장인자-베타2(TGFb2)에 의한 세포 변화를 감소시킬 수 있음을 입증하여 항산화 능력을 증가시키면 TM에서 특징적인 녹내장성 변화의 발생률을 낮추는 데 도움이 될 수 있음을 시사했습니다 [61]. 흥미롭게도 최근에는 윌리엄스와 동료들이 니코틴아마이드 아데닌 디뉴클레오티드(NAD)의 전구체인 비타민 B3(니코틴아마이드) 또는 Nmnat1(니코틴아마이드/니코틴산 단핵구 아데닐릴 트랜스퍼라제 1) 유전자 치료제의 경구 투여가 노화된 마우스에서 미토콘드리아 취약성을 줄이고 녹내장을 예방한다는 사실을 입증했습니다[11].

3. Coenzyme Q

Coenzyme Q is an essential cofactor of the electron transport chain, a membrane stabilizer, and a cofactor in the production of adenosine triphosphate (ATP) by oxidative phosphorylation [36, 62]. Coenzyme Q is endowed with potent antioxidant properties that have been shown to mediate its neuroprotection [63-65]. Interestingly, several studies demonstrated that the compound protects retinal cells against oxidative stress in vitro and in vivo, as well as prevents retinal damage induced by acute IOP elevation or excitotoxicity in vivo [14, 62, 66, 67]. In this respect, Nucci and Colleagues reported that intraocular administration of coenzyme Q affords neuroprotection in the retina of rats subjected to ischemia/reperfusion preventing glutamate increase observed by microdialysis and this was accompanied by minimization of cell death [66]. Accordingly, Lee and Colleagues reported that the compound also inhibits glutamate excitotoxicity and oxidative stress-mediated mitochondrial alteration in glaucomatous DBA/2J mice [36]. Particularly, coenzyme Q promoted RGC survival, preserved the axons in the optic nerve head and inhibited astroglial activation [36]. Moreover, it prevented the upregulation of NMDA receptor subunit 1 and 2A, SOD2 and heme oxygenase-1 (HO1), and also prevented the apoptotic cell death by decreasing Bax and increasing pBad expression‎. Lee and Colleagues also reported that coenzyme Q preserved mitochondrial DNA content and mitochondrial transcription factor A/ oxidative phosphorylation complex IV protein expression‎ in the retina [36]. Furthermore, Noh and Colleagues demonstrated that coenzyme Q protects optic nerve head (ONH) astrocytes against oxidative stress-mediated mitochondrial dysfunction or alteration in glaucoma and other optic neuropathies [68]. Particularly, coenzyme Q decreased SOD2 immunoreactivity in the ONH astrocytes exposed to H2O2 and promotes mitofilin and peroxisome-proliferator activated receptor-γ coactivator-1 (PGC-1α). Interestingly, Nakajima and Colleagues reported that in cultured retinal ganglion cells (RGC-5), a combination of coenzyme Q and trolox, a water-soluble vitamin E analogue, prevented cell damage more effectively than either agent alone [62]. Accordingly, Parisi and Colleagues reported that administration of coenzyme Q associated with vitamin E in open-angle glaucoma patients shows a beneficial effect on the inner retinal function with consequent enhancement of the visual cortical responses [69]. Concerning the mechanism underlying neuroprotection afforded in glaucoma models by coenzyme Q it is conceivable that a free radical scavenging mechanism is only one of the determinants. In fact, neuroprotection afforded by the compound was far greater than that provided by treatment with vitamin E [66]. The Authors hypothesized that coenzyme Q reduces the detrimental action of ischemia/reperfusion on mitochondrial energy metabolism and, consequently, on the function of glutamate transporters, thus limiting accumulation of extracellular glutamate and preventing apoptotic death of RGC [66]. More recently, in agreement with the latter result, Lulli and Colleagues reported that coenzyme Q increases RGC viability and inhibits apoptosis in response to different apoptotic stimuli such as glutamate, chemical hypoxia and serum withdrawal by preventing mitochondrial depolarization [67]. The opening of the mitochondrial permeability transition pore (PTP) followed by extrusion of apoptogenic molecules to the cytoplasm [70] is recognized as the main trigger of apoptosis. Incidentally, coenzyme Q has been shown to inhibit apoptosis by maintaining PTP in the closed conformation via a mechanism independent from free radical scavenging [71].

코엔자임 Q는 

전자 수송 사슬의 필수 보조 인자이자 막 안정제이며 

산화적 인산화에 의한 아데노신 삼인산(ATP) 생성의 보조 인자입니다 [36, 62]. 

코엔자임 Q에는 신경 보호를 매개하는 것으로 밝혀진 

강력한 항산화 특성이 부여되어 있습니다[63-65]. 

흥미롭게도 여러 연구에서 

이 화합물이 시험관 및 생체 내 산화 스트레스로부터 망막 세포를 보호하고 

생체 내 급성 안압 상승 또는 흥분 독성에 의해 유발되는 망막 손상을 예방한다는 사실이 입증되었습니다 [14, 62, 66, 67]. 

이와 관련하여 누치와 동료들은 코엔자임 Q의 안구 내 투여가 허혈/재관류를 받은 쥐의 망막에서 신경 보호를 제공하여 미세 투석으로 관찰된 글루타메이트 증가를 방지하며, 이는 세포 사멸의 최소화를 수반한다고 보고했습니다 [66]. 이에 따라 Lee와 동료들은 이 화합물이 녹내장 DBA/2J 마우스에서 글루타메이트 흥분 독성 및 산화 스트레스 매개 미토콘드리아 변화를 억제한다고 보고했습니다 [36]. 특히 코엔자임 Q는 RGC 생존을 촉진하고 시신경 머리의 축삭을 보존하며 성상교세포 활성화를 억제했습니다 [36]. 또한 NMDA 수용체 서브유닛 1과 2A, SOD2, 헴 산소화 효소-1(HO1)의 상향 조절을 막고, Bax를 감소시키고 pBad 발현을 증가시켜 세포 사멸을 막았습니다. Lee와 동료들은 또한 코엔자임 Q가 망막에서 미토콘드리아 DNA 함량과 미토콘드리아 전사인자 A/산화 인산화 복합체 IV 단백질 발현을 보존한다고 보고했습니다 [36]. 또한 노와 동료들은 코엔자임 Q가 녹내장 및 기타 시신경 병증에서 산화 스트레스 매개 미토콘드리아 기능 장애 또는 변화로부터 시신경 머리(ONH) 성상교세포를 보호한다는 사실을 입증했습니다 [68]. 

특히 코엔자임 Q는 

H2O2에 노출된 ONH 성상교세포에서 

SOD2 면역 반응성을 감소시키고 

미토필린과 퍼옥시좀-증식인자 활성화 수용체-γ 코액티베이터-1(PGC-1α)을 촉진합니다. 

흥미롭게도 나카지마와 동료들은 

배양된 망막 신경절 세포(RGC-5)에서 

코엔자임 Q와 수용성 비타민 E 유사체인 트롤록스의 조합이 두 약제 단독보다 

세포 손상을 더 효과적으로 예방한다고 보고했습니다[62]. 

따라서 파리시와 동료들은 개방각 녹내장 환자에서 비타민 E와 관련된 코엔자임 Q를 투여하면 결과적으로 시각 피질 반응이 향상되어 망막 내부 기능에 유익한 효과를 보인다고 보고했습니다 [69]. 코엔자임 Q가 녹내장 모델에서 제공하는 신경 보호의 기본 메커니즘과 관련하여 자유 라디칼 제거 메커니즘은 결정 요인 중 하나에 불과하다고 생각할 수 있습니다. 실제로 이 화합물이 제공하는 신경 보호 효과는 비타민 E로 치료했을 때보다 훨씬 컸습니다[66]. 저자들은 코엔자임 Q가 미토콘드리아 에너지 대사에 대한 허혈/재관류의 해로운 작용을 감소시키고 결과적으로 글루타메이트 수송체의 기능에 영향을 주어 세포 외 글루타메이트의 축적을 제한하고 RGC의 세포 사멸을 방지한다는 가설을 세웠습니다 [66]. 최근에는 후자의 결과와 일치하여 Lulli와 동료들은 코엔자임 Q가 미토콘드리아 탈분극을 방지하여 글루타메이트, 화학적 저산소증 및 혈청 철수와 같은 다양한 세포 사멸 자극에 대한 반응으로 RGC 생존력을 증가시키고 세포 사멸을 억제한다고 보고했습니다 [67]. 미토콘드리아 투과성 전이 기공(PTP)의 개방과 세포질로의 세포 사멸 유도 분자의 압출[70]이 세포 사멸의 주요 방아쇠로 인식되고 있습니다. 또한 코엔자임 Q는 자유 라디칼 제거와는 독립적인 메커니즘을 통해 PTP를 닫힌 형태로 유지함으로써 세포 사멸을 억제하는 것으로 나타났습니다 [71].

4. Flavonoids

Flavonoids are a large family of phytonutrient compounds widely distributed in fruits and vegetables as well as in chocolate and red wine [72-74]. These compounds have been shown to demonstrate anti-inflammatory and neuroprotective effects that may reduce damage from oxidative stress [75, 76]. Flavonoids exert beneficial effects on multiple disease states, including cancer, cardiovascular disease, and neurodegenerative disorders [73, 77-79]. Interestingly, several studies in vivo and in vitro also reported the beneficial effects of flavonoids in ocular diseases [80-84], however, a recent meta-analysis showed no statistically significant effect of flavonoids on lowering intraocular pressure [85]. Nakayama and Colleagues [86] investigated the neuroprotective potential of three types of flavonoid compounds—kaempferol 3-O-rutinoside (nicotiflorin), quercetin 3-O-rutinoside (rutin), and quercetin 3-Orhamnoside (quercitrin)—using rat primary-isolated RGCs cultured under three kinds of stress conditions: hypoxia, excessive glutamate levels, and oxidative stress. Under these conditions all compounds significantly increased the RGC survival rate but nicotiflorin and rutin were more active than quercitrin [86]. Moreover, rutin significantly inhibited the induction of caspase-3 under both hypoxia and excessive glutamate stress, as well as blocking the induction of calpain during oxidative stress [86]. Interestingly, resveratrol, a naturally occurring polyphenol found in berries, nuts, and red wine, can enhance stress resistance and exerts antiinflammatory, anti-oxidant, and anti-apoptotic effects [87-89]. In this respect, Luna and Colleagues investigated the effects of chronic administration of resveratrol on the expression‎ of markers for inflammation, oxidative damage, and cellular senescence in primary TM cells subjected to chronic oxidative stress [90]. Interestingly, resveratrol treatment prevented increased production of intracellular ROS, IL1α, IL6, IL8, and ELAM-1 [90]. Moreover, it reduced expression‎ of the senescence markers sa-β-gal, lipofuscin, and accumulation of carbonylated proteins. In addition, the compound, exerted antiapoptotic effects that were not associated with a decrease in cell proliferation [90]. Moreover, Chen and Colleagues investigated the role of peroxisome proliferator activated receptor-γ co-activator 1α (PGC-1α) in resveratrol-triggered mitochondrial biogenesis for preventing apoptosis in a retinal ganglion cell line RGC-5 [91]. The Authors reported that resveratrol promoted the protein expression‎ of SIRT1, facilitated PGC-1α translocation from the cytoplasm to the nucleus and up-regulated NRF1 and TFAM [91]. More recently, Lindsey and Colleagues, using an optic nerve crush model, reported that long-term dietary resveratrol treatment delays RGC dendrite remodeling and loss after optic nerve injury and alters the expression‎ of the unfolded protein response BiP, CHOP, and XBP [92]. A number of studies also investigated the potential effects of epigallocatechin-3-gallate (EGCG), the major catechin found in green tea. For example, Zhang and Colleagues reported that EGCG attenuates damaging influences to the retina caused by ischemia/reperfusion and significantly reduced the apoptosis induced by H2O2 in cultured RGCs [82]. In addition, Xie and Colleagues reported a neuroprotective effect of EGCG in an optic nerve crush model in rats [93]. Moreover, Peng and Colleagues demonstrated that administration of EGCG prior to axotomy promotes RGC survival in rats [94]. The neuroprotective capacity of EGCG appears to act through nitric oxide, anti-apoptotic, and cell survival signaling pathways [94]. More recently, Jin and Colleagues reported that key bioactive compounds in green tea leaves (EGCG, theanine and caffeine), attenuate the injury of retinal ganglion RGC-5 induced by H2O2 and ultraviolet radiation [95]. Interestingly, the Authors reported that caffeine and theanine both protected RGC-5 cells from injury as well as enhanced their recovery, while EGCG only protected the cells from injury and did not help them to recover [95].

Ginkgo biloba (Ginkgoaceae) is an ancient species of tree similar to plants which were living 270 million years ago. Ginkgo biloba leaves also contain many different flavonoids, including polyphenolic flavanoids which have been proven to exert antioxidative properties by delivering electrons to free radicals [96]. The extract from the leaves of ginkgo biloba, named as ginkgo biloba extract 761 (EGb761), has been shown to be beneficial for cognitive impairment and dementia [97]. Interestingly, a number of studies suggested a helpful effect of ginkgo biloba for the treatment of glaucoma [98-100]. For example, Hirooka and Colleagues reported RGC neuroprotection by ginkgo biloba extract in rats after IOP elevation [101]. In addition, Ma and Colleagues reported that intraperitoneal injections of ginkgo biloba extract given prior to and daily after an experimental and standardized optic nerve crush in rats were associated with a higher survival rate of retinal ganglion cells [102, 103]. However, it has remained unclear how ginkgo biloba may help RGC to survive after the optic nerve crush. In addition, in contrast to previous studies, recently, Guo and Colleagues, reported no significant improvements in visual field defects and contrast sensitivity in Chinese patients with normal tension glaucoma after four weeks of oral treatment with ginkgo biloba extract [104]. Nevertheless, Shim and colleague reported that systemic administration of Bilberry anthocyanins and Ginkgo biloba extract improves visual function in some individuals with NTG [105].

플라보노이드는 과일과 채소뿐만 아니라 초콜릿과 적포도주에도 널리 분포하는 식물 영양소 화합물의 큰 계열입니다 [72-74]. 이러한 화합물은 산화 스트레스로 인한 손상을 줄일 수 있는 항염증 및 신경 보호 효과를 입증한 것으로 나타났습니다 [75, 76]. 플라보노이드는 암, 심혈관 질환, 신경 퇴행성 질환을 포함한 여러 질병 상태에 유익한 효과를 발휘합니다 [73, 77-79]. 흥미롭게도 생체 내 및 시험관 내 여러 연구에서 안구 질환에 대한 플라보노이드의 유익한 효과를 보고했지만[80-84], 최근 메타 분석에 따르면 플라보노이드가 안압을 낮추는 데 통계적으로 유의미한 영향을 미치지 않는 것으로 나타났습니다[85]. Nakayama와 동료들[86]은 저산소증, 과도한 글루타메이트 수치, 산화 스트레스의 세 가지 스트레스 조건에서 배양된 쥐 일차 분리 RGC를 사용하여 세 가지 유형의 플라보노이드 화합물인 켐페롤 3-O-루티노사이드(니코티플로린), 케르세틴 3-O-루티노사이드(루틴) 및 케르세틴 3-오람노사이드(퀘르시트린)의 신경 보호 가능성을 조사했습니다. 이러한 조건에서 모든 화합물이 RGC 생존율을 유의하게 증가시켰지만 니코티플로린과 루틴은 케르시트린보다 더 활성이 높았습니다[86]. 

또한, 루틴은 저산소증과 과도한 글루타메이트 스트레스 모두에서 카스파제-3의 유도를 유의하게 억제하고 산화 스트레스 동안 칼파인의 유도를 차단했습니다 [86]. 흥미롭게도 베리류, 견과류, 적포도주에서 발견되는 자연 발생 폴리페놀인 레스베라트롤은 스트레스 저항력을 높이고 항염증, 항산화 및 항세포 사멸 효과를 발휘할 수 있습니다 [87-89]. 이와 관련하여 Luna와 동료들은 만성 산화 스트레스를 받은 원발성 TM 세포에서 레스베라트롤의 만성 투여가 염증, 산화 손상 및 세포 노화에 대한 마커의 발현에 미치는 영향을 조사했습니다 [90]. 흥미롭게도 레스베라트롤 처리는 세포 내 ROS, IL1α, IL6, IL8 및 ELAM-1의 생산 증가를 방지했습니다 [90]. 또한 노화 마커인 sa-β-gal, 리포푸신의 발현과 탄화 단백질의 축적을 감소시켰습니다. 또한, 이 화합물은 세포 증식 감소와 관련이 없는 항세포사멸 효과를 나타냈습니다 [90]. 또한 Chen과 동료들은 망막 신경절 세포주 RGC-5에서 세포 사멸을 방지하기 위한 레스베라트롤 유발 미토콘드리아 생물 생성에서 퍼옥시좀 증식인자 활성화 수용체-γ 공동 활성제 1α(PGC-1α)의 역할을 조사했습니다 [91]. 저자들은 레스베라트롤이 SIRT1의 단백질 발현을 촉진하고 세포질에서 핵으로의 PGC-1α 전위를 촉진하며 NRF1과 TFAM을 상향 조절한다고 보고했습니다 [91]. 최근에는 Lindsey와 동료들이 시신경 분쇄 모델을 사용하여 장기간의 식이 레스베라트롤 치료가 시신경 손상 후 RGC 수상돌기 재형성 및 손실을 지연시키고 펼쳐진 단백질 반응 BiP, CHOP 및 XBP의 발현을 변화시킨다고 보고했습니다 [92]. 녹차의 주요 카테킨인 에피갈로카테킨-3-갈레이트(EGCG)의 잠재적 효과에 대해서도 여러 연구에서 조사되었습니다. 예를 들어, Zhang과 동료들은 EGCG가 허혈/재관류로 인한 망막 손상을 완화하고 배양된 RGC에서 H2O2에 의해 유도된 세포 사멸을 현저히 감소시킨다고 보고했습니다 [82]. 또한 Xie와 동료들은 쥐의 시신경 분쇄 모델에서 EGCG의 신경 보호 효과를 보고했습니다 [93]. 또한, Peng과 동료들은 절제술 전에 EGCG를 투여하면 쥐의 RGC 생존이 촉진된다는 사실을 입증했습니다 [94]. EGCG의 신경 보호 능력은 산화 질소, 항 세포 사멸 및 세포 생존 신호 경로를 통해 작용하는 것으로 보입니다 [94]. 최근에 Jin과 동료들은 녹차 잎의 주요 생리 활성 화합물(EGCG, 테아닌, 카페인)이 H2O2와 자외선에 의해 유도된 망막 신경절 RGC-5의 손상을 약화시킨다고 보고했습니다[95]. 흥미롭게도 저자들은 카페인과 테아닌이 RGC-5 세포를 손상으로부터 보호하고 회복을 향상시키는 반면, EGCG는 세포를 손상으로부터만 보호하고 회복에는 도움이 되지 않는다고 보고했습니다 [95].

은행나무(은행과)는 2억 7천만 년 전에 살았던 식물과 유사한 고대 종의 나무입니다. 은행나무 잎에는 자유 라디칼에 전자를 전달하여 항산화 특성을 발휘하는 것으로 입증된 폴리페놀 플라바노이드를 포함한 다양한 플라보노이드가 함유되어 있습니다 [96]. 은행나무 잎에서 추출한 은행나무 추출물 761(EGb761)은 인지 장애와 치매에 도움이 되는 것으로 나타났습니다 [97]. 흥미롭게도 은행잎이 녹내장 치료에 도움이 된다는 연구 결과도 다수 발표되었습니다[98-100]. 예를 들어, Hirooka와 동료들은 안압 상승 후 쥐에서 은행나무 추출물에 의한 RGC 신경 보호 효과를 보고했습니다 [101]. 또한 Ma와 동료들은 쥐의 실험적이고 표준화된 시신경 분쇄술 전과 후 매일 은행나무 추출물을 복강 내 주사하면 망막 신경절 세포의 생존율이 높아진다고 보고했습니다[102, 103]. 그러나 은행잎이 시신경 분쇄 후 망막 신경절 세포의 생존에 어떻게 도움이 되는지는 아직 명확하지 않습니다. 또한, 이전 연구와 달리 최근 Guo와 동료들은 은행나무 추출물로 4주 동안 경구 치료한 후 정상 긴장 녹내장을 가진 중국 환자에서 시야 결손과 대비 감도가 크게 개선되지 않았다고 보고했습니다 [104]. 그럼에도 불구하고 심과 동료들은 빌베리 안토시아닌과 은행나무 추출물을 전신 투여하면 일부 NTG 환자의 시각 기능이 개선된다고 보고했습니다 [105].

5. Citicoline

Citicoline is a natural constituent of all cells, where it serves as the intermediate in phosphatidylcholine synthesis [106]. Citicoline attenuates free fatty acids release and re-establishes levels of cardiolipin phospholipid component of the inner mitochondrial membrane [107]. Citicoline also increase neurotrasmitters levels in the central nervous system [108] and in retina [109]. Interestingly, a number of studies reported citicoline may induce an improvement of the retinal and of the visual pathway function in patients with glaucoma [110-114]. Neuroprotective properties of citicoline have been shown in various experimental model of glaucoma. For example, in partial crush injury of the rat optic nerve model, citicoline was found effective in rescuing RGC and their axons in vivo against delayed degeneration triggered by optic nerve crush [115]. Particularly, the Authors reported that citicoline increased retinal expression‎ of the apoptotic regulating protein Bcl-2, indicating one of the mechanisms which may be engaged in the neuroprotective effect of the compound [115]. Moreover, after intravitreal injection of kainic acid (KA), citicoline counteracted increased expression‎ of NOS isoforms [116] and decreased ERK1/2 kinase activation [117] caused by KA. Using murine retinal explants Oshitari and Colleagues have shown that citicoline can rescue damaged RGCs through an anti- apoptotic effect probably acting as a BDNF mimic [118, 119]. This effect was correlated with the reduction of the expression‎ of active forms of caspases-9 and -3 [119].

시티콜린은 

모든 세포의 천연 구성 성분으로 

포스파티딜콜린 합성의 중간체 역할을 합니다 [106]. 

시티콜린은 

유리 지방산 방출을 약화시키고 

미토콘드리아 막 내부의 카디오리핀 인지질 성분의 수준을 다시 설정합니다 [107]. 

또한 시티콜린은 

중추신경계[108]와 망막[109]의 신경전달물질 수치를 증가시킵니다. 

흥미롭게도 많은 연구에서 

시티콜린이 녹내장 환자의 망막과 시각 경로 기능 개선을 유도할 수 있다고 보고했습니다 [110-114]. 

시티콜린의 신경 보호 특성은 녹내장의 다양한 실험 모델에서 나타났습니다. 예를 들어, 쥐 시신경 모델의 부분적 분쇄 손상에서 시티콜린은 시신경 분쇄에 의해 유발된 지연된 퇴행으로부터 생체 내 RGC와 축삭을 구하는 데 효과적인 것으로 나타났습니다 [115]. 특히 저자들은 시티콜린이 세포 사멸 조절 단백질인 Bcl-2의 망막 발현을 증가시켜 이 화합물의 신경 보호 효과에 관여할 수 있는 메커니즘 중 하나를 나타냈다고 보고했습니다 [115]. 또한, 케인산(KA)의 유리체 내 주입 후 시티콜린은 KA로 인한 NOS 이소폼의 발현 증가[116]와 ERK1/2 키나아제 활성화 감소[117]를 상쇄했습니다. 오시타리와 동료들은 쥐 망막 이식체를 사용하여 시티콜린이 BDNF 모방 물질로 작용하는 항세포사멸 효과를 통해 손상된 RGC를 구할 수 있음을 보여주었습니다[118, 119]. 이 효과는 활성 형태의 카스파제-9 및 -3의 발현 감소와 상관관계가 있었습니다 [119].

6. Polyunsatured Fatty Acids

Omega 3 (ω-3) and omega 6 (ω-6) are polyunsaturated essential fatty acids (PUFAs). Both fatty acids are concentrated in the phospholipids of cell membranes throughout the human body, but especially in the brain, heart, retina, and testes [120]. Essential fatty acids omega 3 and omega 6 are of special interest due to their reported anti-inflammatory, antithrombotic, hypolipidemic, and vasodilatory capacities [121, 122]. Interestingly, recent studies suggest a key role for PUFAs also in neurodegeneration and neuropsychiatric diseases [123, 124]. Dietary deficiencies in ω-3 polyunsaturated fatty acids are also known to effect retinal function including RGC activity whereas a diet rich in ω-3 PUFA helps to reduce vulnerability of RGCs to dysfunction induced by IOP stress [125]. Nguyen and Colleagues demonstrated that an increased consumption of omega-3 fatty acids leads to decreased IOP through an increased aqueous outflow facility via prostaglandins (PGs) [126]. In fact, PGs, are metabolites of omega-3 fatty acids [127] and reduce IOP by enhancing uveoscleral and trabecular outflow via direct effects on ciliary muscle relaxation and remodeling of extracellular matrix [128]. Cod liver oil that contains vitamin A and both the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has been demonstrated to lower IOP in experimental animals [129]. Moreover, a number of studies reported that omega-3 fatty acids prevented retinal cell structural degradation and counteracted glial cell activation induced by the elevation of IOP [130]. Accordingly, Nguyen and Colleagues, also reported that dietary ω-3 deficiency and repeat acute IOP insult are additive risk factors for RGC dysfunction [131]. Interestingly, a diet with increased omega-3 and decreased omega-6 could favor an increase in IOP reducing synthesis of PG-F2, leading to a decrease in uveoscleral outflow [132]. Conversely, a diet high in omega 6 and low in omega 3 to be associated with a reduced occurrence of POAG [133]. Therefore, it is important to have an appropriate balance between these fatty acid families [130, 134]. Accordingly, Pérez de Arcelus and Colleagues, in a prospective cohort study found that a diet with a high omega 3:6 ratio intake, thus low in omega 6, was associated with a higher occurrence of glaucoma [134]. Interestingly, Tourtas and Colleagues, reported in cultivated human TM cells, that ω-6 was efficient in preventing H2O2 mediated anti-proliferative effects, but displayed a repressive effect on mitochondrial activity and proliferation [135]. For ω-3, the Authors observed no negative side effects but an effective potential to prevent H2O2 mediated anti-proliferative/-metabolic effects [135]. Nevertheless, Schnebelen and Colleagues demonstrated that a 6-month supplementation with a combination of omega-3 and omega-6 PUFAs is more effective than single supplementations, since the EPA plus DHA plus gamma-linolenic acid dietary combination prevented retinal cell structure and decreased glial cell activation induced by the elevation of IOP in rats [130].

7. Taurine

Taurine (2-aminoethylsuphonic acid) is a “semi-essential” sulfur amino acid structurally similar to the neurotransmitters glycine and gamma aminobutyric acid (GABA) [136, 137]. Taurine is the most abundant free amino acid in mammalian retina after glutamate [138, 139]. The source of taurine is mostly exogenous and meats, seafood and fish are the major sources of this amino acid [140]. Taurine intake from dietary sources is highly dependent on taurine transporter expression‎ in tissues exhibiting a high retinal uptake index (26.6% in serum) [141]. In retinal cells, taurine uptake was demonstrated in photoreceptors, retinal ganglion cells, retinal glial cells and in the retinal pigment epithelium cells [142-145]. Though the exact role of taurine in the retina is not fully understood, several studies have reported that taurine had a protective effect on cells from neuroretina [146] and retinal pigment epithelium [147]. The exact mechanism of this protective effect is still unknown. Taurine is considered to be an antioxidant, but the mechanisms underlying its antioxidant properties have never been clearly characterized, particularly in retinal cells [137].

However, activation of GABAA receptors through taurine binding may decrease neuronal vulnerability to excitotoxic damage [146]. Moreover, Bulley and Shen found that taurine reduces glutamate-induced Ca2+ influx via ionotropic glutamate receptors and voltage-dependent Ca2+ channels in the neurons, and the effect of taurine was selectively inhibited by strychnine and picrotoxin, but not GABA receptor antagonists, although GABA receptors were present in the neurons [136]. Interestingly, taurine supplementation in rats has demonstrated to reduce neuronal and glial cell death in different pathological conditions [148-150]. In cats, taurine supplementation has been found to prevent the progressive degeneration of retinal photoreceptors seen in retinitis pigmentosa [151]. In the retina, decreased taurine uptake was also found to induce retinal degeneration [152-159]. Retinal degeneration has been extensively investigated in taurine free-diet fed cats [152-156, 159] and monkeys [157]. The taurine depletion was also induced in cats and rats by treatments with taurine transport inhibitors, such as β-alanine or guanidoethane sulfonate (GES) [158, 160]. At the level of RGCs, Gaucher and Colleagues observed a significant loss induced by the GES treatment [161]. This retinal ganglion cell degeneration in GES-treated mice was very similar to that obtained in vigabatrin-treated neonatal rats [150], which was already attributed to the taurine depletion. Accordingly, taurine supplementation prevented vigabatrin-induced RGC degeneration [150]. Moreover, Froger and Colleagues demonstrated that taurine can improve RGC survival in culture or in different animal models of RGC degeneration [162]. Particularly, taurine effect on RGC survival was assessed in vitro on primary pure RCG cultures under serum-deprivation conditions, and on NMDA-treated retinal explants from adult rats [162]. In vivo, taurine was administered through the drinking water in two glaucomatous animal models (DBA/2J mice and rats with vein occlusion) and in a model of retinitis pigmentosa with secondary RGC degeneration (P23H rats). Taurine significantly enhanced RGCs survival and partly prevented NMDA-induced RGC excitotoxicity [162]. Moreover, taurine supplementation increased RGC densities both in DBA/2J mice, in rats with vein occlusion and in P23H rats [162]. This study indicates that enriched taurine nutrition can directly promote RGC survival and provides evidence that taurine can positively interfere with retinal degenerative diseases. More recently, Han and Colleagues suggested that taurine neuroprotection may result from inhibition of NADPH oxidases, the primary source of superoxide induced by NMDA receptor activation, probably in a calcium-dependent manner [163].

타우린(2- 아미노에틸설폰산)은 

신경전달물질인 글리신 및 

감마 아미노부티르산(GABA)과 구조적으로 유사한 "준필수" 유황 아미노산입니다[136, 137]. 

타우린은 포유류 망막에서 글루타메이트 다음으로 가장 풍부한 유리 아미노산입니다 [138, 139]. 

타우린의 공급원은 대부분 외인성이며 육류, 해산물 및 생선이 이 아미노산의 주요 공급원입니다 [140]. 식이 공급원을 통한 타우린 섭취는 높은 망막 흡수 지수(혈청 내 26.6%)를 보이는 조직에서 타우린 수송체 발현에 크게 의존합니다[141]. 

망막 세포에서 타우린 흡수는 

광수용체, 망막 신경절 세포, 망막 신경교 세포 및 망막 색소 상피 세포에서 입증되었습니다 [142-145]. 

망막에서 타우린의 정확한 역할은 완전히 이해되지 않았지만, 여러 연구에서 타우린이 신경망막 [146]과 망막 색소 상피 [147]의 세포를 보호하는 효과가 있다고 보고했습니다. 이 보호 효과의 정확한 메커니즘은 아직 밝혀지지 않았습니다. 타우린은 항산화제로 간주되지만, 특히 망막 세포에서 타우린의 항산화 특성의 근본적인 메커니즘은 명확하게 밝혀지지 않았습니다 [137].

그러나 타우린 결합을 통한 GABAA 수용체의 활성화는 흥분성 손상에 대한 신경세포의 취약성을 감소시킬 수 있습니다 [146]. 또한 Bulley와 Shen은 타우린이 뉴런의 이온성 글루타메이트 수용체와 전압 의존성 Ca2+ 채널을 통해 글루타메이트 유발 Ca2+ 유입을 감소시키고, 뉴런에 GABA 수용체가 존재하더라도 타우린의 효과는 스트라이크닌과 피크로톡신에 의해 선택적으로 억제되지만 GABA 수용체 길항제는 억제되지 않는다는 것을 발견했습니다 [136]. 흥미롭게도 쥐에게 타우린을 보충하면 다양한 병리학적 조건에서 신경세포와 신경교세포 사멸이 감소하는 것으로 나타났습니다 [148-150]. 고양이의 경우 타우린 보충제는 망막색소변성증에서 나타나는 망막 광수용체의 점진적인 퇴행을 예방하는 것으로 밝혀졌습니다 [151]. 망막에서 타우린 섭취 감소도 망막 변성을 유도하는 것으로 밝혀졌습니다[152-159]. 타우린이 없는 사료를 먹인 고양이[152-156, 159]와 원숭이[157]에서 망막 변성이 광범위하게 조사되었습니다. 타우린 고갈은 β-알라닌 또는 구아니도에탄 설포네이트(GES)와 같은 타우린 수송 억제제 처리에 의해서도 고양이와 쥐에서 유도되었습니다 [158, 160]. 고셔와 동료들은 RGC 수준에서 GES 처리에 의해 유도된 상당한 손실을 관찰했습니다 [161]. GES 처리된 쥐의 망막 신경절 세포 퇴화는 이미 타우린 고갈에 기인한 비가바트린 처리된 신생아 쥐[150]에서 얻은 것과 매우 유사했습니다. 따라서 타우린 보충제는 비가바트린으로 인한 RGC 변성을 예방했습니다[150]. 또한 Froger와 동료들은 타우린이 배양 또는 다양한 RGC 퇴화 동물 모델에서 RGC 생존을 개선할 수 있음을 입증했습니다 [162]. 특히, 혈청 결핍 조건에서 일차 순수 RCG 배양체와 성인 쥐의 NMDA 처리 망막 이식체에서 타우린이 RGC 생존에 미치는 영향을 시험관 내에서 평가했습니다 [162]. 생체 내에서 타우린은 두 가지 녹내장 동물 모델(DBA/2J 마우스와 정맥 폐색이 있는 쥐)과 이차성 RGC 변성이 있는 망막색소변성 모델(P23H 쥐)에서 식수를 통해 투여되었습니다. 타우린은 RGC의 생존을 크게 향상시키고 NMDA에 의한 RGC 흥분 독성을 부분적으로 예방했습니다 [162]. 또한 타우린을 보충하면 DBA/2J 마우스, 정맥 폐색이 있는 쥐, P23H 쥐 모두에서 RGC 밀도가 증가했습니다 [162]. 이 연구는 풍부한 타우린 영양이 RGC 생존을 직접적으로 촉진할 수 있으며 타우린이 망막 퇴행성 질환을 긍정적으로 방해할 수 있다는 증거를 제시합니다. 최근에 한과 동료들은 타우린 신경 보호가 아마도 칼슘 의존적인 방식으로 NMDA 수용체 활성화에 의해 유도되는 과산화물의 주요 공급원인 NADPH 산화효소의 억제로 인해 발생할 수 있다고 제안했습니다 [163].

8. Alpha-lipoic acid

https://kr.iherb.com/pr/doctor-s-best-alpha-lipoic-acid-600-600-mg-60-veggie-caps/2475

Alpha-lipoic acid (ALA), also known as thioctic acid, is a naturally occurring compound synthesized enzymatically in the mitochondrion but commonly found in dietary components such as vegetables and meats [164]. ALA is a necessary cofactor for mitochondrial α-ketoacid dehydrogenases, and thus serves a critical role in mitochondrial energy metabolism [164, 165]. ALA and its reduced form DHLA, are considered powerful antioxidant agents with a scavenging capacity for many ROS [166, 167] and appears to regenerate other endogenous antioxidants (e.g. vitamins C and E) [164]. In addition, the compounds elicited several cellular actions ranging from metal chelator to a mediator of cell signaling pathways to an insulin mimetic to a hypotriglyceridemic agent, etc. [164, 165]. Although ALA has been mainly studied in diabetic polyneuropathies, it showed beneficial properties for the prevention of vascular disease, hypertension, and inflammation [164, 165]. ALA is currently being tested as a treatment for neurodegeneration and neuropathy in several clinical trials. ALA has been also investigated in glaucoma. For example, Filina and Colleagues reported beneficial properties by ALA in correcting glutathion deficiency, detected in OAG patients by increasing lacrimal SH group level [168]. Particularly, some studies reported that supplementation of lipoic acid can increase glutathione in red blood cells [169] and lacrimal fluid [170] of patients with glaucoma. More recently, using a DBA/2J mouse model of glaucoma, Inman and Colleagues reported that addition of ALA to the diet increased antioxidant gene and protein expression‎ and improved RGC survival without significant IOP changes [35]. Interestingly, Koriyama and Colleagues demonstrated that ALA exerts a neuroprotective effect against oxidative stress in retinal neurons in vitro and in vivo by inducing the expression‎ of heme oxygenase-1 through Kelch-like ECH-associated protein (Keap1) / NF-E2-related factor 2 (Nrf2) signaling [171].

티옥트산으로도 알려진 알파 리포산(ALA)은 

미토콘드리아에서 효소적으로 합성되는 자연 발생 화합물이지만 

채소나 육류와 같은 식이 성분에서 흔히 발견됩니다 [164]. 

ALA는 

미토콘드리아 α-케톤산 탈수소효소에 필요한 보조 인자이므로 

미토콘드리아 에너지 대사에 중요한 역할을 합니다[164, 165]. 

ALA와 그 환원 형태인 DHLA는

 많은 ROS를 제거하는 강력한 항산화제로 간주되며[166, 167], 

다른 내인성 항산화제(예: 비타민 C 및 E)를 재생하는 것으로 보입니다[164]. 

또한, 이 화합물은 금속 킬레이트에서 세포 신호 전달 경로의 매개체, 인슐린 모방체, 저중성지방혈증 치료제 등에 이르는 여러 세포 작용을 유도했습니다. [164, 165]. 

ALA는 

주로 당뇨병성 다발성 신경병증에서 연구되어 왔지만 

혈관 질환, 고혈압 및 염증 예방에 유익한 특성을 보여주었습니다 [164, 165]. 

ALA는 현재 여러 임상 시험에서 신경 퇴화 및 신경 병증 치료제로 시험되고 있습니다. 녹내장에 대한 연구도 진행 중입니다. 예를 들어, 필리나와 동료들은 눈물샘 SH 그룹 수치를 증가시켜 녹내장 환자에서 발견되는 글루타치온 결핍을 교정하는 데 ALA의 유익한 특성을 보고했습니다 [168]. 특히 일부 연구에서는 리포산을 보충하면 녹내장 환자의 적혈구[169]와 눈물샘[170]에서 글루타치온을 증가시킬 수 있다고 보고했습니다. 최근에는 녹내장의 DBA/2J 마우스 모델을 사용하여 Inman과 동료들은 식이에 ALA를 첨가하면 항산화 유전자 및 단백질 발현이 증가하고 안압에 큰 변화 없이 RGC 생존율이 향상된다고 보고했습니다 [35]. 흥미롭게도 Koriyama와 동료들은 ALA가 켈치 유사 ECH 관련 단백질(Keap1)/NF-E2 관련 인자 2(Nrf2) 신호를 통해 헴 옥시게나제-1의 발현을 유도함으로써 시험관 및 생체 내 망막 뉴런의 산화 스트레스에 대해 신경 보호 효과를 발휘한다는 사실을 입증했습니다 [171].

9. Forskolin

https://kr.iherb.com/pr/life-extension-forskolin-10-mg-60-vegetarian-capsules/49696

Forskolin is a diterpenoid isolated from plant Coleus forskohlii (Lamiaceae). Forskolin can penetrate cell membranes and stimulates the enzyme adenylate cyclase [172] decreasing IOP by reducing aqueous humor inflow in animals [173-176] and humans [173, 177-179] suggesting potential use for glaucoma treatment. Interestingly, oral administration of forskolin in association with rutina or with rutina and vitamins B1 and B2 contributed to IOP control [180] and could act in synergy with topical pharmacological treatments in POAG patients [181]. Interestingly, a number of studies suggested that forskolin promotes neuronal survival by stimulating neurotrophin activity in models of RGC death [182, 183]. Particularly, Intravitreal injection of forskolin with brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) contributed to survival and axonal regeneration of RGCs in adult cats [184]. Recently, Russo and Colleagues reported that forskolin prevents RGC loss induced by ischemia-reperfusion in rats and homotaurine and L-carnosine potentiate forskolin neuroprotection [185]. The treatment with forskolin/ homotaurine/ L-carnosine reduced calpain activation and increased Akt activation and GSK-3β phosphorylation in the retina subjected to ischemia/reperfusion [185]. The observed neuroprotection it was independent from PKA activation and distinct from the hypotensive effects of forskolin. Interestingly, Mutolo and Colleagues reported that a combined administration of forskolin, homotaurine, carnosine, and folic acid in POAG patients with their IOP compensated by topical drugs, induced a significant further decrease of IOP and an improvement of Pattern Electroretinogram (PERG) amplitude [186].

10. Curcumin

Curcumin is a polyphenol isolated from the plant Curcuma Longa (Zingiberaceae) and is the principal curcuminoid of the popular spice turmeric. Curcumin, has been widely used in many countries for centuries both as a spice and as a medicine [187]. In the past decade, several bio-functions of curcumin have been identified, including its anti-inflammatory effects, antitumorigenesis effects, antioxidative activity, and its inhibitory effects on histone aectyltransferases. Concerning its antioxidative activity, several studies have proven that curcumin inhibits oxidative and nitrative DNA damage by inhibiting the stress-induced elevated levels of 8-hydroxydeoxyguanosine (a biomarker of DNA oxidation) and 8-nitroguanine [188, 189]. Curcumin also inhibits oxidative damage by regulating oxygen consumption, ATP content, calcium retention, mitochondrial membrane potential, the activities of mitochondrial respiratory complexes I, II, III, and V, and mitochondrial respiratory capacity [190, 191]. Recently, in a chronic IOP rat model, pretreatment of curcumin protected against RGC loss and was correlated with significantly increased cell viability of BV-2 microglia [192]. In another research, staurosporine-induced ganglion cell death was attenuated by low dosages of curcumin both in vitro and in vivo [193]. Moreover, in an acute IOP model in rat, curcumin pretreatment was able to reverse the decrease of mitofusin 2 (mfn2), a mitochondrial fusion protein, and increase nuclear factor erythroid 2-related factor 2 (Nrf2) in the retinal I/R-induced open-angle glaucoma model in vivo, indicating that the compound could maintain the normal mitochondrial function and alleviate the retinal I/R injury by regulating the antioxidant system [194]. Interestingly, curcumin significantly attenuated NMDA-induced apoptosis in retinal neuronal/glial cultures in vitro by inhibiting the NR1 subunit of the NMDA receptor phosphorylation and NMDAR-mediated Ca2C increase [195]. More recently, the same Authors confirmed the neuroprotective activity of curcumin against NMDA toxicity, possibly related to an increased level of NR2A [196]. Interestingly, using TM cells as in vitro model system, Lin and Wu reported that curcumin treatment protected TM cells against oxidative stress-induced cell death [197]. In addition, curcumin pretreatment significantly inhibited proinflammatory factors, including IL-6, ELAM-1, IL-1α, and IL-8, whereas it decreased activities of senescence marker SA-β-gal, and lowered levels of carbonylated proteins and apoptotic cell numbers [197].

11. ERIGERON BREVISCAPUS

Erigeron breviscapus (vant.) Hand. Mazz. (EBHM) is a widely used Chinese medicinal plant for heart disease [198]. Its major active compounds are scutellarin, 1,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid and erigoster B [199]. EBHM has been suggested as neuroprotectant in glaucoma. Particularly, some studies have shown that Erigeron breviscapus could improve the activity of cytochrome oxidase in RGCs [200] and optic nerve axoplasmic transport in rat models of acute elevated IOP [201]. Interestingly, in the experimental optic nerve crush model in rats, EBHM treatment increased the survival rate of the RGC and was able to rescue and/or restore the injured RGCs [202]. Moreover, administration of EBHM solution partially protected RGC loss in NMDA-induced retinal neuronal injury in rats [203]. EBHM extract also showed a partial protective effect on the visual field of glaucoma patients with controlled IOP [204]. In addition, Erigeron breviscapus extract treatment improved the impaired visual function (detected by multifocal electroretinogram) of persistently elevated IOP in rats [205]. Although it is not known to which components of EBHM are attributed the specific effects, it has been suggested that the combined activity and a certain interdependency of several active constituents of EBHM extract are responsible for its beneficial effects [206, 207]. For example, Bastianetto and collegues reported that the flavonoid fraction strongly inhibited both the toxicity and the free radical accumulation induced by sodium nitroprusside and/or 3-morpholinosydnonimine [208]. Several studies also showed neuroprotective effect of scutellarin and other ingredients extracted from Erigeron breviscapus against neuronal damage following cerebral ischemia/reperfusion [209-213]. Interestingly, Wang and Colleagues observed that scutellarin inhibited lipopolysaccharide (LPS)-induced production of proinflammatory mediators and suppressed LPS-stimulated inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), and IL-1β mRNA expression‎ in rat primary microglia or BV-2 mouse microglial cell line [212]. More recently, Yin and Colleagues, reported that DSX, an active component extracted from Erigeron breviscapus, suppress outward potassium channel currents in rat RGCs, suggesting it may be one of the possible mechanisms underlying Erigeron breviscapus prevents vision loss and RGC damage caused by glaucoma [214].

12. LYCIUM BARBARUM

Lycium barbarum L. belongs to the Solanaceae family (also named Fructus Lycii or called Wolfberry or Goji berries). It has been used for centuries as a traditional medicinal and food supplement in East Asia, however, since the beginning of the 21st century, wolfberries have become increasingly popular in Europe and North America [215, 216]. The active components in wolfberry include L. barbarum polysaccharides (LBP), zeaxanthine, betaine, cerebroside and trace amounts of zinc, iron, and copper [217]. LBP are the primary active components and have been reported to possess a wide array of pharmacological activities [216, 218]. It has been reported that LBP exerts beneficial effects in animal models of ocular diseases. For example, several studies have shown neuroprotective effects of LBP on RGCs in acute model of glaucoma [219, 220]. Particularly, Mi and Colleagues reported that Lycium barbarum polysaccharides protect RGCs and retinal vasculature in a mouse model of acute ocular hypertension and provide neuroprotection by down-regulating receptors for advanced glycation end products (RAGE), endothelin-1 (ET-1), amyloid-beta peptide and advanced glycation end products (AGE) in the retina, as well as their related signaling pathways [219]. He and Colleagues demonstrated that LBPs elicit retino- and neuro-protective effects via the activation of nuclear factor erythroid 2-related factor (Nrf2) and upregulation of expression‎ of heme oxygenase-1 (HO1) [220]. Lycium barbarum have shown neuroprotective effect also in chronic ocular hypertension model of glaucoma [221-223] and MCAO-induced ischemic retina [218]. Particularly, Chan and Colleagues suggested that the neuroprotective effect of LBPs in chronic ocular hypertension (COH) rats is partly due to modulating the activation of microglia [221], whereas Chiu and Colleagues suggested that the prosurvival effect of LBPs on rat RGCs in COH may be mediated by an increase in the upregulation of βB2 crystalline, a neuroprotective agent [223]. In addition, Li and Colleagues reported that LBP reduces secondary degeneration of RGCs after partial optic nerve transection suggesting that this effect may be linked to the inhibition of oxidative stress and the JNK/c-jun pathway in the retina [224].

CONCLUSION

Glaucoma it is not always under the control of currently available drugs, thus a need exists for novel therapies able to save retinal ganglion cells from injury or to repair damaged neurons. Nutraceuticals may offer some therapeutic potential in glaucoma management, however the lack of well designed clinical trials examining their benefits for glaucoma limits their current therapeutic use. The finding of appropriate use of nutraceuticals that may be able to modify the risk of glaucoma may provide insight into glaucoma pathogenesis and decrease the need for, and therefore the side effects from, conventional therapies.

CONSENT FOR PUBLICATION

Not applicable.

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ACKNOWLEDGEMENTS

All the authors contributed substantially to the design, performance, analysis, or reporting of the work equally.

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CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

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