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Open AccessReview
Targeting Glutamate Neurotoxicity through Dietary Manipulation: Potential Treatment for Migraine
by
Fahimeh Martami
1 and
Kathleen F. Holton
1,2,3,*
1
Department of Health Studies, American University, Washington, DC 20016, USA
2
Department of Neuroscience, American University, Washington, DC 20016, USA
3
Center for Neuroscience and Behavior, American University, Washington, DC 20016, USA
*
Author to whom correspondence should be addressed.
Nutrients 2023, 15(18), 3952; https://doi.org/10.3390/nu15183952
Submission received: 16 August 2023 / Revised: 8 September 2023 / Accepted: 9 September 2023 / Published: 12 September 2023
Abstract
Glutamate, the main excitatory neurotransmitter in the central nervous system, is implicated in both the initiation of migraine as well as central sensitization, which increases the frequency of migraine attacks. Excessive levels of glutamate can lead to excitotoxicity in the nervous system which can disrupt normal neurotransmission and contribute to neuronal injury or death. Glutamate-mediated excitotoxicity also leads to neuroinflammation, oxidative stress, blood-brain barrier permeability, and cerebral vasodilation, all of which are associated with migraine pathophysiology. Experimental evidence has shown the protective effects of several nutrients against excitotoxicity. The current review focuses on the mechanisms behind glutamate’s involvement in migraines as well as a discussion on how specific nutrients are able to work towards restoring glutamate homeostasis. Understanding glutamate’s role in migraine is of vital importance for understanding why migraine is commonly comorbid with widespread pain conditions and for informing future research directions.
중추 신경계의 주요 흥분성 신경 전달 물질인
글루타메이트는
편두통의 시작과 편두통 발작의 빈도를 증가시키는
중추 민감화 모두에 관여합니다.
과도한 수준의 글루타메이트는
신경계에 흥분 독성을 유발하여
정상적인 신경 전달을 방해하고
신경 세포 손상이나 사망에 이르게 할 수 있습니다.
글루타메이트 매개 흥분 독성은 또한
신경 염증, 산화 스트레스, 혈액-뇌 장벽 투과성, 뇌 혈관 확장으로 이어지며,
이 모든 것이 편두통 병리 생리와 관련이 있습니다.
실험적 증거에 따르면
흥분성 독성에 대한
여러 영양소의 보호 효과가 입증되었습니다.
이번 리뷰에서는
편두통에 글루타메이트가 관여하는 메커니즘과
특정 영양소가 글루타메이트 항상성을 회복하는 데
어떻게 작용할 수 있는지에 대한 논의에 초점을 맞추고자 합니다.
편두통에서
글루타메이트의 역할을 이해하는 것은
편두통이 일반적으로 광범위한 통증 질환과 동반되는 이유를 이해하고
향후 연구 방향을 제시하는 데 매우 중요합니다.
Keywords:
1. Introduction
Migraine is a common neurological disorder with prevalence rates ranging from 9–16% worldwide [1]. This disorder primarily occurs during the most productive years of adulthood, from age 20 to 50 years [2]. According to the latest report from the Global Burden of Disease study, migraine is the primary cause of disability among people less than 50 years of age [3]. In 2016, the annual cost of healthcare utilization and lost productivity associated with migraine in the US was estimated at $36 billion [4]. Migraine is associated with a wide spectrum of comorbidities including gastrointestinal, psychiatric, cardiac, and cerebrovascular disorders, which can increase the physiological burden [5]. Despite the profound impact of migraine, it is still underdiagnosed and undertreated [6,7].
The pathophysiological mechanism underlying migraine is not completely understood. However, activation and sensitization of meningeal nociceptors in the trigeminovascular (TG) system are widely accepted as a key pathway in the initiation of a migraine attack [8]. The TG system is comprised of sensory neurons that originate from the trigeminal ganglion that innervate cerebral blood vessels including the dura mater, the outermost layer of the meninges [9].
Evidence supports the role of glutamate neurotransmission in both the activation and perpetuation of migraine [10,11]. Peripheral release of glutamate is involved in the generation of migraine pain through N-methyl-D-aspartate (NMDA) receptors found in the meningeal afferents of the trigeminal nerve [12]. High glutamatergic activity also leads to increased cerebral excitability and resultant cortical spreading depression (CSD) that can cause nociception in the dura mater [10,13]. Interestingly, in addition to the direct effect of glutamate in the activation of trigeminal nociceptors and the contribution to CSD development, it is also contributing to pain sensitization as well. Previous reports have indicated that the production and release of the vasodilatory neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) can be induced by increased glutamatergic neurotransmission [14,15]. Perivascular release of these neuropeptides can eventually lead to a phenomenon called “neurogenic inflammation” which is believed to be an underlying element leading to sensitization of trigeminal meningeal nociceptors [16]. Central sensitization has been observed in migraine and can lead to contact allodynia (i.e., pain from a stimulus that does not ordinarily cause pain) [17]. Central sensitization is an augmentation of membrane excitability through upregulation of glutamatergic neurotransmission, which contributes to pain hypersensitivity in many pain conditions [18]. The NMDA glutamate receptor is pivotal for both the initiation and maintenance of central sensitization, and thus, in reverse, is also thought to be the key in stopping this process [19]. A high concentration of glutamate in the synaptic cleft can lead to excitotoxicity, which is the over-excitation of neurons which leads to apoptosis, or cell death [20]. Excitotoxicity causes oxidative stress and inflammation in the central nervous system (CNS). The reinforcing properties between excitotoxicity, oxidative stress, and neuroinflammation (the “neurotoxic triad”) have been implicated in neurologic disorders including chronic pain and migraine [21]. Thus, disorders such as migraine may benefit from interventions targeting glutamate specifically.
Therefore, in the current review, we aim to combine existing knowledge about the role of glutamate in migraine pathogenesis along with information on nutrients that are protective against glutamate excitotoxicity, and then end with a proposed dietary treatment for migraine management.
1. 소개
편두통은
전 세계적으로 유병률이
9~16%에 이르는 흔한 신경 질환입니다[1].
이 질환은 주로
20세부터 50세까지 가장 생산적인 성인기에 발생합니다[2].
글로벌 질병 부담 연구의 최신 보고서에 따르면
편두통은 50세 미만에서 장애를 일으키는
주요 원인입니다[3].
2016년 미국에서 편두통으로 인한 연간 의료 이용 및 생산성 손실 비용은 360억 달러로 추산되었습니다[4]. 편두통은 위장, 정신, 심장, 뇌혈관 질환을 포함한 광범위한 동반 질환과 연관되어 있어 생리적 부담을 증가시킬 수 있습니다[5]. 편두통의 심각한 영향에도 불구하고 편두통은 여전히 진단과 치료가 제대로 이루어지지 않고 있습니다[6,7].
편두통의 근본적인 병태생리학적 메커니즘은 완전히 이해되지 않았습니다.
그러나
삼차신경계(TG) 시스템에서
수막성 통각 수용체의 활성화와 감작이
편두통 발작의 주요 경로로 널리 알려져 있습니다 [8].
TG 시스템은
뇌수막의 가장 바깥층인 경막을 포함한
뇌혈관을 자극하는 삼차신경절에서 유래하는
감각 신경세포로 구성되어 있습니다 [9].
편두통의 활성화와 지속 모두에서
글루타메이트 신경전달의 역할을 뒷받침하는 증거가 있습니다[10,11].
글루타메이트의 말초 방출은
삼차 신경의 수막 구심성에서 발견되는
N-메틸-D-아스파르트산염(NMDA) 수용체를 통해
편두통의 발생에 관여합니다 [12].
또한
높은 글루탐산 활성은
대뇌 흥분성을 증가시키고
결과적으로 경질막에서 통각을 유발할 수 있는
대뇌 피질 확산 우울증(CSD)으로 이어집니다[10,13].
흥미롭게도
글루타메이트는
삼차신경통각 수용체의 활성화와 CSD 발달에 기여하는 직접적인 효과 외에도
통증 민감화에도 기여하고 있습니다.
이전 보고에 따르면
혈관 확장성 신경 펩티드인 칼시토닌 유전자 관련 펩타이드(CGRP)와
물질 P(SP)의 생성 및 방출은
글루타메이트 신경 전달 증가에 의해
이러한
신경 펩타이드의 혈관 주위 방출은
결국 삼차 수막성 통각 수용체의 감작을 유발하는 근본적인 요소로 여겨지는
"신경성 염증"이라는 현상을 초래할 수 있습니다 [16].
편두통에서 중추 감작이 관찰되었으며
접촉성 이질통(즉, 일반적으로 통증을 유발하지 않는 자극에 의한 통증)을 유발할 수 있습니다[17].
중추 감작화는
글루타메이트 신경전달의 상향 조절을 통해
막 흥분성을 증가시키는 것으로,
많은 통증 질환에서 통증 과민성을 유발합니다 [18].
NMDA 글루타메이트 수용체는
중추 감작의 시작과 유지에 중추적인 역할을 하므로
역으로 이 과정을 막는 데도 핵심적인 역할을 하는 것으로 생각됩니다 [19].
시냅스 틈새에 글루타메이트 농도가 높으면
뉴런이 과도하게 흥분하여
세포 사멸 또는 세포 사멸로 이어지는 흥분 독성을 유발할 수 있습니다 [20].
흥분 독성은
중추 신경계(CNS)에 산화 스트레스와 염증을 유발합니다.
흥분성 독성, 산화 스트레스, 신경 염증
(" “neurotoxic triad 신경 독성 삼중주") 사이의 강화 특성은
만성 통증과 편두통을 포함한 신경 장애와 관련이 있습니다 [21].
따라서
편두통과 같은 질환은
글루타메이트를 표적으로 하는 중재의 혜택을 받을 수 있습니다.
따라서
이번 리뷰에서는
편두통 발병에서 글루타메이트의 역할에 대한 기존 지식과
글루타메이트 흥분 독성으로부터 보호하는 영양소에 대한 정보를 결합한 다음
편두통 관리를 위한 식이 치료법을 제안하는 것으로 마무리하고자 합니다.
2. Glutamatergic Neurotransmission
Glutamate is the main mediator of excitatory neurotransmission in the brain. It has two types of receptors, ionotropic and metabotropic [22]. Ionotropic glutamate receptors (iGluRs) are ligand-gated channels subcategorized into NMDA, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and the kainic acid (KA) receptor, which all have fast excitatory effects. Metabotropic receptors (mGluRs) are G-protein-coupled receptor channels. Eight metabotropic receptors have been characterized (mGluR1-8) and fall into three groups (group I-III) based on their similarity regarding second messenger systems and pharmacology, with group I being associated with slow excitation, and groups II and III being more associated with slow inhibition [22].
Glutamate receptors are found throughout the body; therefore, dysregulation of the glutamatergic system can impose a broad range of effects [22]. In the nervous system, glutamate is implicated in crucial aspects of normal brain function including synaptogenesis, learning, cognition, and memory [23,24]. As mentioned above, the iGluRs are involved in fast synaptic responses to glutamate, while the mGluRs play a role in slow neuromodulatory signaling [25]. Although these receptors have local and functional variability, glutamate excitotoxicity targets both families of receptors [25]. Excitotoxicity results from the excessive synaptic release of glutamate and the consequent accumulation of high concentrations of free calcium (Ca2+) in the cytosol [26] which is mediated by NMDA receptors [26]. However, AMPA and KA receptors can also contribute to Ca2+ overload through their partial permeability to Ca2+ [26]. The mGluRs function in two ways, by directly increasing cytosolic Ca2+ levels via the facilitation of Ca2+ release from the intracellular stores, and indirectly by promoting NMDA receptor migration to the cell membrane [27]. Excitotoxicity is one of the leading causes of neuronal damage and death, and this process has been implicated in a variety of neurological diseases including schizophrenia, Alzheimer’s, Parkinson’s, multiple sclerosis (MS), epilepsy, chronic pain, and migraine [28,29,30,31,32,33].
2. 글루타메이트 신경 전달
글루타메이트는
뇌에서 흥분성 신경전달의 주요 매개체입니다.
여기에는 두 가지 유형의 수용체, 즉 이온성 및 대사성 수용체가 있습니다 [22].
이온성 글루타메이트 수용체(iGluR)는
리간드 게이트 채널로
NMDA,
α-아미노-3-하이드록시-5-메틸-4-이소옥사졸 프로피오네이트(AMPA),
카이닌산(KA) 수용체로 세분되며
모두 빠른 흥분 효과를 가지고 있습니다.
메타보트로픽 수용체(mGluR)는
G 단백질 결합 수용체 채널입니다.
8개의 메타보트로픽 수용체가 특성화되었으며(mGluR1-8), 2차 전달 체계 및 약리학적 유사성에 따라 세 그룹(그룹 I-III)으로 분류되는데, 그룹 I은 느린 흥분과 관련이 있고 그룹 II와 III은 느린 억제와 더 관련이 있습니다 [22].
글루타메이트 수용체는
몸 전체에서 발견되므로
글루타메이트 시스템의 조절 장애는 광범위한 영향을 미칠 수 있습니다[22].
신경계에서 글루타메이트는
시냅스 형성, 학습, 인지 및 기억을 포함한
정상적인 뇌 기능의 중요한 측면에 관여합니다 [23,24].
위에서 언급했듯이
iGluR은 글루타메이트에 대한 빠른 시냅스 반응에 관여하는 반면,
mGluR은 느린 신경 조절 신호에 관여합니다 [25].
이러한 수용체는
국소적이고 기능적으로 가변적이지만
글루타메이트 흥분 독성은 두 수용체군을 모두 표적으로 삼습니다 [25].
흥분 독성은
글루타메이트의 과도한 시냅스 방출과
그에 따른 세포질 내 고농도의 유리 칼슘(Ca2+)의 축적으로 인해 발생하며,
이는 NMDA 수용체[26]에 의해 매개됩니다[26].
그러나
AMPA 및 KA 수용체도 Ca2+에 대한 부분적인 투과성을 통해
Ca2+ 과부하에 기여할 수 있습니다 [26].
mGluR은
세포 내 저장소로부터 Ca2+ 방출을 촉진하여
세포질 Ca2+ 수준을 직접적으로 증가시키고,
NMDA 수용체의 세포막 이동을 촉진하여
간접적으로 증가시키는 두 가지 방식으로 기능합니다 [27].
흥분성 독성은
신경세포 손상과 사망의 주요 원인 중 하나이며
이 과정은 정신분열증, 알츠하이머, 파킨슨병, 다발성 경화증(MS), 간질, 만성 통증, 편두통 등
다양한 신경 질환과 관련이 있습니다[28,29,30,31,32,33].
3. Physiological and Anatomical Evidence Related to the Role of Glutamate in Migraine
Figure 1 illustrates the mechanisms involving glutamate in the pathogenesis of migraine (which is reviewed in detail in this section).
3. 편두통에서 글루타메이트의 역할과 관련된 생리적 및 해부학적 증거
그림 1은 편두통의 발병에 글루타메이트가 관여하는 메커니즘을 보여줍니다(이 섹션에서 자세히 살펴봅니다).
Figure 1. Mechanisms explaining the role of glutamate in migraine pathogenesis.
3.1. Role of Glutamate in Nociception
The trigeminal system (in addition to C1 and C2 fibers) comprises all of the nociceptive neurotransmission within the head [34]. C1 and C2 fibers refer to the first and second cervical spinal nerves that, along with second-order neurons of the trigeminal nucleus caudalis, comprise the trigeminocervical complex [8]. Nociceptive signals from the meninges and cervical roots are sent to higher-order brain regions including the brainstem, hypothalamus, basal ganglia, and thalamus [8]. Projection of trigeminovascular thalamic neurons to different areas of the cortex contributes to pain perception as well as migraine-associated symptoms [8]. Glutamate has a well-known role in the transmission of nociceptive signals from primary sensory afferents to second-order neurons in the brainstem [35].
Interestingly, evidence from preclinical studies has shown that all types of glutamate receptors are characterized and found in the trigeminal system [36,37,38,39]. In line with these findings, other studies have also indicated that the administration of glutamate leads to hyperalgesia [40,41] while inhibition of glutamate blocks its nociceptive effects [42]. An interesting in vivo experiment explored the role of peripherally released glutamate in the generation of migraine pain by using trigeminal neurons from animal models [12]. They found that glutamate and aspartate (another amino acid with a similar structure that also functions as a neurotransmitter) can activate NMDA receptors on peripheral sensory trigeminal ganglion neurons in meningeal nerve terminals and that they can induce excitation of meningeal afferents implicated in the generation of migraine pain [12]. Thus, glutamate can lead to trigeminal nociception in two ways: (1) via signal transmission from primary meningeal nerves to higher brain regions, which results in cortical excitability, and (2) via activation of NMDA receptors in tissues located outside of the blood-brain barrier (BBB), which consequently leads to trigeminal nociception [12].
3.1. 통각 수용에서 글루타메이트의 역할
삼차신경계(C1 및 C2 섬유 외에도)는
머리 안의 모든 통각 신경 전달을 구성합니다[34].
C1 및 C2 섬유는
삼차신경핵의 2차 뉴런과 함께 삼차경추 복합체를 구성하는
제1 및 제2 경추 척수 신경을 말합니다[8].
수막과 경추의 통각 신호는 뇌간, 시상하부, 기저핵, 시상을 포함한 상위 뇌 영역으로 전달됩니다 [8]. 삼차 혈관 시상 뉴런이 피질의 다른 영역으로 투사되는 것은 편두통 관련 증상뿐만 아니라 통증 지각에 기여합니다 [8]. 글루타메이트는 일차 감각 수용체에서 뇌간의 이차 뉴런으로 통각 신호를 전달하는 데 잘 알려진 역할을 합니다 [35].
흥미롭게도 전임상 연구의 증거에 따르면 모든 유형의 글루타메이트 수용체가 삼차신경계에서 특징적으로 발견되는 것으로 나타났습니다 [36,37,38,39]. 이러한 연구 결과에 따라 다른 연구에서도 글루타메이트를 투여하면 통각 과민증이 유발되고[40,41], 글루타메이트를 억제하면 통각 효과를 차단한다는 사실이 밝혀졌습니다[42]. 흥미로운 생체 내 실험에서는 동물 모델의 삼차 신경세포를 사용하여 편두통 발생에서 말초 방출된 글루타메이트의 역할을 탐구했습니다[12].
연구진은 글루타메이트와 아스파르트산염(신경 전달 물질로 기능하는 유사한 구조를 가진 또 다른 아미노산)이 뇌수막 신경 말단에서 말초 감각 삼차 신경절 뉴런의 NMDA 수용체를 활성화하고 편두통 발생과 관련된 뇌수막 구심체의 흥분을 유도할 수 있다는 것을 발견했습니다 [12]. 따라서 글루타메이트는 (1) 일차 뇌수막 신경에서 더 높은 뇌 영역으로 신호를 전달하여 피질 흥분성을 초래하고 (2) 혈액뇌장벽(BBB) 외부에 위치한 조직의 NMDA 수용체를 활성화하여 결과적으로 삼차 통각 수용을 유발하는 두 가지 방식으로 삼차 통각 수용을 유발할 수 있습니다 [12].
3.2. Role of Glutamate in Cortical Spreading Depression
Glutamate is also proposed as a key player in the initiation of CSD, which is an expanding wave of depolarization (activation of neurons) followed by a wave of hyperpolarization (inactivity of neurons while concentration gradients re-set) across the cortex [43,44]. Preclinical evidence supports the role of CSD in stimulating trigeminal neurons [45]. Local release of glutamate by neurons is assumed to trigger CSD [46]. CSD is recognized as the biological reason for migraine aura which has been further confirmed with the observation of CSD waves in migraine aura patients [47]. The latest version of the International Classification of Headache Disorders (ICHD) (Third edition) defines migraine aura as an “early symptom of an attack, believed to be the manifestations of focal cerebral dysfunction, typically lasting 20–30 min and precedes the headache” [48]. Visual aura is, by far, the most prevalent type of aura [49].
3.2. 대뇌피질 확산 우울증에서 글루타메이트의 역할
글루타메이트는
또한 피질 전체에 걸쳐 확장되는 탈분극(뉴런의 활성화) 파동에 이어
과분극(뉴런의 비활성화와 농도 구배가 다시 설정되는 동안의 뉴런 비활성화) 파동인 C
SD의 시작에 핵심적인 역할을 하는 것으로 제안됩니다 [43,44].
전임상 증거는
삼차신경세포를 자극하는
CSD의 역할을 뒷받침합니다[45].
뉴런에 의한 글루타메이트의 국소 방출은 CSD를 유발하는 것으로 추정됩니다 [46]. CSD는 편두통 아우라의 생물학적 원인으로 인식되고 있으며, 편두통 아우라 환자에서 CSD 파의 관찰을 통해 더욱 확인되었습니다 [47].
최신 버전의 국제 두통 장애 분류(ICHD)(제3판)에서는 편두통 아우라를 "일반적으로 20~30분 동안 지속되며 두통에 선행하는 국소 뇌기능 장애의 징후로 여겨지는 발작의 초기 증상"으로 정의하고 있습니다[48]. 시각적 아우라는 지금까지 가장 널리 퍼진 아우라 유형입니다[49].
3.3. Role of Glutamate in Central Sensitization
The intensity and duration of headache attacks are attributed to the development of central sensitization [50]. Central sensitization is defined as abnormal amplification in central nociceptive processing because of increases in membrane excitability as well as reduced inhibition [50]. Central sensitization is observed in both chronic and episodic migraine [51]. Excitotoxicity is considered a major player in the onset and continuation of central sensitization [15]. This is thought to occur via the upregulation of NMDA and AMPA receptors on the primary afferent neurons, with a subsequent reduction in the threshold for neuronal activation, which contributes to the onset of central sensitization [52]. Higher levels of glutamate in plasma have been observed in both chronic and episodic migraine patients as compared to healthy controls, with no significant difference between chronic and episodic migraineurs [53]. Cutaneous allodynia, which is highly prevalent in migraine patients, is a clinical manifestation of central sensitization [54]. Interestingly, cutaneous allodynia has been associated with response to preventive treatment, with severe occurrence being associated with decreased response to treatment [55,56,57]. This evidence supports the important role of central sensitization in migraine pathophysiology.
3.3. 중추 감작에서 글루타메이트의 역할
두통 발작의 강도와 지속 시간은
중추 감작의 발달에 기인합니다 [50].
중추 감작이란
막 흥분성의 증가와 억제 감소로 인한
중추 통각 처리의 비정상적인 증폭으로 정의됩니다 [50].
중추 감작화는
만성 편두통과 삽화성 편두통 모두에서 관찰됩니다 [51].
흥분성 독성은 중추 감작의 시작과 지속에 중요한 역할을 하는 것으로 간주됩니다 [15]. 이는 일차 구심성 뉴런의 NMDA 및 AMPA 수용체의 상향 조절을 통해 발생하는 것으로 생각되며, 이후 뉴런 활성화의 역치가 감소하여 중추 감작의 시작에 기여합니다 [52]. 건강한 대조군에 비해 만성 편두통 환자와 삽화 편두통 환자 모두에서 혈장 내 글루타메이트 수치가 더 높은 것으로 관찰되었으며, 만성 편두통과 삽화 편두통 사이에 큰 차이는 없었습니다 [53].
편두통 환자에서 매우 흔한 피부 이질통은 중추 감작의 임상 증상입니다 [54]. 흥미롭게도 피부 이질통은 예방 치료에 대한 반응과 관련이 있으며, 심한 발생은 치료에 대한 반응 감소와 관련이 있습니다 [55,56,57]. 이러한 증거는 편두통 병리 생리학에서 중추 감작의 중요한 역할을 뒷받침합니다.
3.4. Role of Glutamate in Disruption of the Blood-Brain Barrier (BBB)
The integrity of the BBB guarantees a unique environment for the CNS by controlling what substances can enter and leave the CNS [58]. Therefore, disruption of the BBB allows the influx of potentially toxic substances into the brain. BBB permeability can occur via the overactivation of NMDA receptors which causes excitotoxicity [59], but other events such as head trauma [60], infection [61], neurotoxic exposures [62], high stress [63], neuroinflammation [64], and oxidative stress [65] can also lead to permeability of the BBB. The contribution of neuroinflammation and oxidative stress, which are tightly tied to excitotoxicity, will be described in more detail below.
Increased glutamatergic neurotransmission in migraine leads to the sustained secretion of vasoactive substances including CGRP and SP [66]. These neuropeptides contribute to vasodilation, plasma protein extravasation, mast cell activation, and the release of proinflammatory cytokines, resulting in a phenomenon called neurogenic inflammation [16], which, as mentioned above, can lead to BBB permeability [67].
In neurons, the influx of excess Ca2+ into the cell following the activation of glutamate receptors eventually leads to the production of free radicals (atoms missing an electron) which are called reactive oxygen species (ROS) and reactive nitrogen species (RNS) [68]. Further support for this idea is provided by electron paramagnetic resonance spectroscopy showing that NMDA receptor activation results in the production of superoxide radicals [69]. Typically, ROS and RNS are counteracted by antioxidants or antioxidant enzyme systems within the cell, which have the ability to donate an electron to re-balance the free radicals. If the amount of free radicals outstrips the antioxidant defense system of the cell, oxidative stress occurs [70]. These free radicals can start a cascade of events including mitochondrial impairment, and damage to lipids, proteins, and DNA, leading to mutagenesis, and ultimately cell death [71]. Additionally, as mentioned above, oxidative stress can lead to BBB permeability [65].
Increased permeability of the BBB in migraine patients could result in the entry of blood-borne toxins, as well as increased amounts of dietary glutamate and aspartate, into the brain, which could elicit excitotoxicity. It is noteworthy that excitotoxicity, neuroinflammation, and oxidative stress have the ability to perpetuate one another, allowing this “neurotoxic triad” to be maintained over time. Thus, neurogenic inflammation and oxidative stress can also be involved in migraine initiation/sensitization through potentiating excitotoxicity.
3.4. 혈액-뇌 장벽(BBB) 파괴에서 글루타메이트의 역할
BBB의 무결성은 CNS에 들어오고 나갈 수 있는 물질을 제어하여 CNS에 고유한 환경을 보장합니다 [58]. 따라서 BBB가 파괴되면 잠재적으로 독성이 있는 물질이 뇌로 유입될 수 있습니다. BBB 투과성은 흥분성 독성을 유발하는 NMDA 수용체의 과활성화를 통해 발생할 수 있지만 [59] 두부 외상 [60], 감염 [61], 신경독성 노출 [62], 높은 스트레스 [63], 신경 염증 [64], 산화 스트레스 [65] 등의 다른 사건도 BBB의 투과성을 유발할 수 있습니다. 흥분성 독성과 밀접한 관련이 있는 신경염증과 산화 스트레스의 기여에 대해서는 아래에서 자세히 설명합니다.
편두통에서 글루탐산성 신경전달이 증가하면 CGRP와 SP를 포함한 혈관 활성 물질이 지속적으로 분비됩니다 [66]. 이러한 신경 펩타이드는 혈관 확장, 혈장 단백질 혈관 외 유출, 비만 세포 활성화 및 염증성 사이토카인의 방출에 기여하여 신경성 염증 [16]이라는 현상을 초래하며, 위에서 언급했듯이 BBB 투과성을 유발할 수 있습니다 [67].
뉴런에서 글루타메이트 수용체가 활성화된 후 세포 내로 과도한 Ca2+가 유입되면 결국 활성 산소종(ROS)과 활성 질소종(RNS)이라고 하는 자유 라디칼(전자가 빠진 원자)이 생성됩니다 [68]. 전자 상자성 공명 분광학은 NMDA 수용체 활성화가 슈퍼옥사이드 라디칼을 생성한다는 사실을 보여줌으로써 이 아이디어를 더욱 뒷받침합니다 [69]. 일반적으로 ROS와 RNS는 세포 내의 항산화제 또는 항산화 효소 시스템에 의해 상쇄되는데, 이 시스템은 전자를 기증하여 활성산소의 균형을 다시 맞추는 능력을 가지고 있습니다. 자유 라디칼의 양이 세포의 항산화 방어 시스템을 능가하면 산화 스트레스가 발생합니다[70]. 이러한 활성산소는 미토콘드리아 손상, 지질, 단백질, DNA 손상 등 일련의 사건을 일으켜 돌연변이 유발, 궁극적으로는 세포 사멸로 이어질 수 있습니다[71]. 또한 위에서 언급한 바와 같이 산화 스트레스는 BBB 투과성으로 이어질 수 있습니다[65].
편두통 환자의 BBB 투과성이 증가하면 혈액 매개 독소와 식이 글루타메이트 및 아스파르트산염의 양이 증가하여 뇌로 유입되어 흥분 독성을 유발할 수 있습니다.
흥분성 독성, 신경 염증 및 산화 스트레스는
서로 지속되는 능력이 있어 이 '신경 독성 삼중주'가
시간이 지나도 유지될 수 있다는 점에
주목할 필요가 있습니다.
따라서
신경성 염증과 산화 스트레스는
흥분 독성을 강화하여 편두통의 시작/감작에 관여할 수 있습니다.
3.5. Role of Glutamate in Nitric Oxide Release and Vasodilation
A link between glutamate and nitric oxide (NO) was initially proposed after the finding that glutamate or NMDA treatment causes the release of NO and cyclic guanosine monophosphate (cGMP) in cerebellar cultures [72]. Additionally, NMDA receptor activation results in a rise in cGMP levels in the brain, with nitric oxide synthase (NOS) inhibitors and NO scavengers preventing this rise in cGMP levels [72]. This suggests that NO has signaling functions downstream of NMDA receptor activation. In neurons, Ca2+ entry, as a result of the activation of NMDA receptors, induces NOS, which is physically coupled to NMDA receptors [73]. Glutamate can also activate NMDA receptors in the endothelial cells of capillaries, causing subsequent induction of NOS, and release of NO, which causes vasodilation [74]. The contribution of cerebral and meningeal arterial vasodilation in migraine initiation has been suspected for many decades [75,76]. Interestingly, NO can negatively affect the BBB when it combines with a superoxide radical to form peroxynitrite, a potent free radical that leads to oxidative stress and excitotoxicity [77,78,79].
3.5. 산화질소 방출 및 혈관 확장에서 글루타메이트의 역할
글루타메이트와 산화질소(NO) 사이의 연관성은 글루타메이트 또는 NMDA 처리가 소뇌 배양에서 NO와 사이클릭 구아노신 모노포스페이트(cGMP)의 방출을 유발한다는 사실을 발견한 후 처음 제안되었습니다[72]. 또한 NMDA 수용체가 활성화되면 뇌에서 cGMP 수치가 상승하며, 산화질소 합성효소(NOS) 억제제와 NO 제거제는 이러한 cGMP 수치 상승을 방지합니다[72]. 이는 NO가 NMDA 수용체 활성화의 하류에 신호 기능을 가지고 있음을 시사합니다. 뉴런에서 NMDA 수용체의 활성화로 인한 Ca2+ 유입은 NMDA 수용체와 물리적으로 결합된 NOS를 유도합니다 [73]. 글루타메이트는 또한 모세혈관 내피 세포에서 NMDA 수용체를 활성화하여 후속적으로 NOS를 유도하고 혈관 확장을 유발하는 NO를 방출할 수 있습니다 [74]. 편두통 시작에서 대뇌 및 수막 동맥 혈관 확장의 기여는 수십 년 동안 의심되어 왔습니다 [75,76]. 흥미롭게도 NO는 과산화 라디칼과 결합하여 산화 스트레스와 흥분 독성을 유발하는 강력한 자유 라디칼인 퍼옥시니트라테를 형성할 때 BBB에 부정적인 영향을 미칠 수 있습니다 [77,78,79].
4. Glutamate Concentration in Migraineurs
Increased levels of glutamate in plasma [80,81,82], cerebrospinal fluid (CSF) [14,82,83], and platelets [84,85,86] have been detected in migraine patients. This elevated level of glutamate was observed during attacks as well as during interictal periods [82,83,87], for those with and without aura [82,88,89]. Furthermore, a meta-analysis on excitatory neuro-metabolite levels across pain conditions, using data pooled from magnetic resonance spectroscopy studies, revealed a significant increase in glutamate levels in the brains of migraine patients, compared with controls [90]. This evidence could reflect cortical neuronal hyperexcitability and points to the dysfunction of glutamatergic signaling in migraine pathogenesis. In a study by Ferrari et al., prophylactic medications lowered the frequency of attacks and glutamate levels compared to baseline; however, migraine sufferers still had higher serum levels of glutamate compared to healthy controls [89]. Another case-control study among migraine patients without aura, using proton magnetic resonance spectroscopy, showed an increased level of the glutamate/glutamine ratio between attacks in both the primary occipital cortex and thalamus [91]. Table 1 represents the glutamate concentration in adult migraine patients, as compared to healthy controls, in various tissues. Significantly higher glutamate concentrations have been reported in the plasma, platelet, CSF, and brain of migraine patients, as compared to healthy controls.
4. 편두통 환자의 글루타메이트 농도
편두통 환자에서 혈장 [80,81,82], 뇌척수액(CSF) [14,82,83], 혈소판 [84,85,86]의 글루타메이트 수치가 증가하는 것이 발견되었습니다. 이러한 글루타메이트 수치의 상승은 발작 시뿐만 아니라 발작 간기[82,83,87], 기운이 있는 사람과 없는 사람 모두에서 관찰되었습니다[82,88,89]. 또한, 자기공명분광학 연구에서 수집한 데이터를 사용하여 통증 상태 전반의 흥분성 신경 대사물질 수치에 대한 메타 분석 결과 편두통 환자의 뇌에서 대조군에 비해 글루타메이트 수치가 크게 증가한 것으로 나타났습니다[90]. 이러한 증거는 대뇌 피질 신경세포의 과흥분성을 반영할 수 있으며 편두통 발병에서 글루타메이트 신호의 기능 장애를 지적합니다. Ferrari 등의 연구에서 예방 약물은 발작 빈도와 글루타메이트 수치를 기준선에 비해 낮추었지만 편두통 환자는 건강한 대조군에 비해 여전히 혈청 글루타메이트 수치가 높았습니다 [89]. 양성자 자기공명 분광법을 사용한 기운이 없는 편두통 환자를 대상으로 한 또 다른 사례 대조 연구에서는 일차 후두피질과 시상 모두에서 발작 사이에 글루타메이트/글루타민 비율의 증가가 나타났습니다 [91]. 표 1은 건강한 대조군과 비교한 성인 편두통 환자의 다양한 조직에서 글루타메이트 농도를 나타냅니다. 편두통 환자의 혈장, 혈소판, CSF 및 뇌에서 건강한 대조군에 비해 훨씬 더 높은 글루타메이트 농도가 보고되었습니다.
Table 1. Glutamate concentrations in migraine patients vs. healthy individuals.
5. Dietary Components Affecting Glutamate Neurotoxicity and Migraine
Dietary factors may be one of the most important modifiable lifestyle components for treating migraines. There are specific micronutrients that protect against excitotoxicity caused by excess glutamate. These same micronutrients have also shown promising efficacy in migraine reduction in clinical settings. These nutrients are reviewed below (Figure 2 illustrates the protective mechanisms for each nutrient against excitotoxicity).
5. 글루타메이트 신경독성과 편두통에 영향을 미치는 식이 성분
식이 요인은 편두통 치료를 위한 가장 중요한 생활 습관 개선 요소 중 하나일 수 있습니다. 과도한 글루타메이트로 인한 흥분성 독성으로부터 보호하는 특정 미량 영양소가 있습니다. 이러한 미량 영양소는 또한 임상 환경에서 편두통 감소에 유망한 효능이 있는 것으로 나타났습니다. 이러한 영양소를 아래에서 살펴봅니다(그림 2는 각 영양소의 흥분성 독성에 대한 보호 메커니즘을 보여줍니다).
Figure 2. Nutrients mechanism in protecting against excitotoxicity.
While outside the scope of this review, it should also be quickly noted that dietary factors can also affect the microbiome and that these important gut bacteria may also be influential in migraine. For a comprehensive review of what is known about the gut-brain axis in migraines, please refer to [97].
그림 2. 흥분성 독성으로부터 보호하는 영양소 메커니즘.
이 리뷰의 범위를 벗어나지만, 식이 요인도 마이크로바이옴에 영향을 미칠 수 있으며 이러한 중요한 장내 세균이 편두통에도 영향을 미칠 수 있다는 점도 빠르게 언급해야 합니다. 편두통의 장-뇌 축에 대해 알려진 내용을 종합적으로 검토하려면 [97]을 참조하세요.
5.1. Omega-3 Fatty Acids
Omega-3 fatty acids are long-chain, polyunsaturated fatty acids that contribute to normal brain development and function [98]. Docosahexaenoic acid (DHA), a very long chain omega-3 fatty acid, has been identified as an important component of the lipid membrane of the CNS and an abundant phospholipid in the gray matter of the cerebral cortex [98]. Besides their structural function, omega-3s are a precursor for signaling molecules, as well as playing a role in neurotransmission and gene expression [99].
Both in vivo and in vitro evidence have shown beneficial effects of omega-3 derivations on nociception [100,101,102]. The essential omega-3 fatty acid, alpha-linolenic acid, showed a neuroprotective effect against glutamate-mediated excitotoxicity, a critical cause of neuronal injury in animal studies, including epilepsy [103], ischemia [104], stroke [105] and spinal cord injury [106]. One of the earliest studies providing evidence regarding the neuroprotective potential of omega-3 fatty acids was derived from an animal study investigating the effect of an omega-3-supplemented diet on neuronal damage, as compared to a control diet (using olive oil). The neuronal injuries were induced by middle cerebral artery occlusion and infusion of an NMDA receptor agonist, by the researchers. Rats supplemented with omega-3s had significantly reduced damage in both focal ischemia and excitotoxicity [107]. The underlying mechanism of this effect could be attributed to the change in membrane fatty acid composition. Arachidonic acid (an omega-6 fatty acid) has been reported to be associated with increased excitotoxicity by inducing a prolonged inhibition of glutamate reuptake into glial cells [108] and also increased release of glutamate into the synaptic cleft [109]. Therefore, substitution of omega-3 fatty acids for omega-6 could offer beneficial effects on excitotoxic brain damage. Additionally, eicosapentaenoic acid (EPA) and DHA (long-chain omega-3s) also showed promising benefits for protecting against monosodium glutamate (MSG) neurotoxicity in the hippocampus of prepubertal rats [110]. This neuroprotective effect of omega-3s could be attributed to their role in enhancing the plasticity, communication, and function of astrocytes [111]. Astrocytes are the major regulators of glutamate homeostasis and prevent excitotoxicity by taking glutamate up out of the synaptic cleft. This effect is supported by the finding that a lack of omega-3s can aggravate the negative impact of aging on astroglial morphology and activity [112]. In summary, omega-3 fatty acids may be effective in reducing excitotoxicity, making this an important class of nutrients for neurological protection.
Epidemiological research has shown an inverse association between dietary intake of omega-3s and the prevalence and characteristics of headache disorders including migraine [113,114]. Human clinical studies that investigated the potential effects of omega-3s on migraine suggest that omega-3 supplementation might improve migraine-related outcomes [115,116,117]. A meta-analysis indicated that omega-3s significantly reduced migraine duration; however, no significant change in terms of frequency or intensity was detected [118].
5.1. 오메가-3 지방산
오메가-3 지방산은 정상적인 두뇌 발달과 기능에 기여하는 장쇄 고도 불포화 지방산입니다[98]. 매우 긴 사슬의 오메가-3 지방산인 도코사헥사에노산(DHA)은 중추신경계 지질막의 중요한 구성 요소이자 대뇌 피질의 회백질에 풍부한 인지질로 확인되었습니다 [98]. 오메가3는 구조적 기능 외에도 신호 분자의 전구체이자 신경 전달 및 유전자 발현에 중요한 역할을 합니다[99].
생체 내 및 시험관 내 증거 모두 오메가-3 유도체가 통각에 유익한 영향을 미치는 것으로 나타났습니다 [100,101,102]. 필수 오메가-3 지방산인 알파리놀렌산은 간질[103], 허혈[104], 뇌졸중[105], 척수 손상[106] 등 동물 연구에서 신경 손상의 중요한 원인인 글루타메이트 매개 흥분 독성에 대한 신경 보호 효과를 보여주었습니다. 오메가-3 지방산의 신경 보호 잠재력에 관한 증거를 제공하는 최초의 연구 중 하나는 오메가-3 보충 식단이 대조 식단(올리브유 사용)과 비교하여 신경 손상에 미치는 영향을 조사한 동물 연구에서 도출되었습니다. 연구진은 중대뇌동맥 폐색과 NMDA 수용체 작용제 주입을 통해 신경세포 손상을 유도했습니다. 오메가3를 보충한 쥐는 국소 허혈과 흥분성 독성 모두에서 손상이 현저히 감소했습니다 [107]. 이 효과의 근본적인 메커니즘은 막 지방산 구성의 변화 때문일 수 있습니다. 아라키돈산(오메가-6 지방산)은 신경교 세포로의 글루타메이트 재흡수를 장기간 억제하고[108] 시냅스 틈새로의 글루타메이트 방출을 증가시켜 흥분성 독성을 증가시키는 것으로 보고되었습니다[109]. 따라서 오메가-6를 오메가-3 지방산으로 대체하면 흥분성 뇌 손상에 유익한 효과를 제공할 수 있습니다. 또한 에이코사펜타엔산(EPA)과 DHA(장쇄 오메가-3)는 사춘기 전 쥐의 해마에서 글루탐산나트륨(MSG) 신경 독성을 보호하는 데 유망한 이점을 보여주었습니다[110]. 오메가3의 이러한 신경 보호 효과는 성상교세포의 가소성, 의사소통 및 기능을 향상시키는 역할 때문일 수 있습니다 [111]. 성상교세포는 글루타메이트 항상성의 주요 조절자이며 시냅스 틈새에서 글루타메이트를 배출하여 흥분성 독성을 방지합니다. 이러한 효과는 오메가3가 부족하면 노화가 성상교세포의 형태와 활동에 미치는 부정적인 영향을 악화시킬 수 있다는 연구 결과에 의해 뒷받침됩니다 [112]. 요약하면, 오메가-3 지방산은 흥분성 독성을 줄이는 데 효과적일 수 있으므로 신경 보호에 중요한 영양소입니다.
역학 연구에 따르면 오메가-3의 식이 섭취와 편두통을 포함한 두통 장애의 유병률 및 특성 사이에는 역의 상관관계가 있는 것으로 나타났습니다 [113,114]. 편두통에 대한 오메가3의 잠재적 효과를 조사한 인체 임상 연구에 따르면 오메가3 보충제가 편두통 관련 결과를 개선할 수 있다고 합니다[115,116,117]. 메타 분석에 따르면 오메가-3는 편두통 지속 시간을 유의하게 줄였지만, 빈도나 강도 측면에서는 유의미한 변화가 발견되지 않았습니다 [118].
5.2. Magnesium (Mg2+)
Magnesium is an important intracellular mineral that plays vital roles in a wide range of metabolic reactions [119]. Magnesium is also critical for normal CNS function. It is involved with nerve transmission, the release of neurotransmitters, and protection against excitotoxicity [120]. Low levels of magnesium have been reported in many neurological disorders including Alzheimer’s disease [121], traumatic brain injury [122], stroke [123], epilepsy [124], Parkinson’s [125], psychiatric disorders [126], and migraine [127]. Low brain magnesium was also detected during a migraine attack using magnetic resonance spectroscopy in migraine patients [128].
There are several mechanisms underlying the anti-nociceptive effect of magnesium especially related to glutamate-mediated excitotoxicity. Magnesium blocks NMDA glutamate receptors, thereby protecting against excitotoxicity, and since NMDA receptor antagonists suppress trigeminal nociceptive transmission, this mineral could be a potential modulator of trigeminovascular nociception [34]. In a rat model of trigeminovascular activation, blocking NMDA receptors with either magnesium or memantine (an antagonist of NMDAR) inhibited nociceptive activation of the trigeminocervical complex [129]. In support of this effect on the NMDA receptor, a reduction in damage was observed in magnesium-treated mice who had induced excitotoxicity by ibotenate, a glutamate receptor agonist [130]. Moreover, in an animal model of cerebral ischemia, the extracellular level of glutamate in the cortex was reduced following magnesium administration [131]. In experimental models, magnesium also had an inhibitory effect on CSD [132,133] and deficiency in this mineral increases the sensitivity of NMDA receptors to glutamate-mediated CSD [134].
The effectiveness of magnesium has been extensively evaluated for migraine prevention. The results of a meta-analysis of randomized clinical trials indicated that oral magnesium significantly alleviated the frequency and severity of migraine, and intravenous magnesium was effective in relieving acute migraine attacks [135]. However, another meta-analysis investigating the effects of intravenous magnesium failed to show a beneficial effect in terms of pain relief [136].
5.3. Vitamin D
Vitamin D is a steroid hormone that is best known for its role in Ca2+ and phosphorus homeostasis and osteogenesis [137]. Notably, the beneficial effects of vitamin D extend well beyond mineral absorption and bone health. It is considered a neurosteroid because of its crucial role in neuronal integrity and brain development [138]. Vitamin D deficiency has been linked to neurological disorders [139]. Vitamin D receptors are broadly found in different parts of the brain including the cortex, hypothalamus, thalamus, hippocampus, and substantia nigra, supporting the potential role of vitamin D in different neurological conditions [140].
In vitro evidence has demonstrated the protective effects of vitamin D against glutamate excitotoxicity [141], which may be partially mediated by vitamin D’s role in gene transcription, affecting the production of key enzymes in the nervous system. Vitamin D deficiency can reduce glutamate decarboxylase levels in the brain. Glutamate decarboxylase is the enzyme that catalyzes the decarboxylation of glutamate to convert it into γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the nervous system [142]. Thus, vitamin D can help prevent excitotoxicity indirectly by upregulating the production of the enzyme that increases the conversion of excitatory glutamate into inhibitory GABA. Notably, vitamin D may also reduce excitotoxicity via modulation of NMDA receptors by regulating Ca2+ influx through L-type voltage-sensitive Ca2+ channels [143].
Epidemiological studies evaluating serum levels of vitamin D in migraine patients have reported conflicting results, with some case-control studies showing no differences between migraine patients and healthy controls [144,145], and others observing significant differences [146,147]. However, a meta-analysis in 2020 summarizing the results from 8 observational studies reported overall significantly lower serum levels of 25(OH)D (the main circulating form of vitamin D) in migraine patients, as compared to healthy controls [148]. Additionally, the concentration of vitamin D in the blood has also been associated with migraine characteristics, as migraine patients with vitamin D deficiency are more likely to suffer frequent and severe attacks than migraine patients with adequate levels of vitamin D [146,149]. Vitamin D administration was found to be effective in alleviating migraine-related outcomes in a meta-analysis of five randomized controlled trials [150].
5.4. Vitamin C
Vitamin C, or ascorbic acid, is a water-soluble vitamin known mostly for its unique antioxidant properties [151]. Vitamin C has a critical role in antioxidant defense as well as many non-antioxidant activities in the CNS [151].
Ascorbic acid exerts a neuroprotective effect against excitotoxicity through attenuating NMDA receptor activity [152] and increasing glutamate reuptake from the synaptic cleft [153]. Vitamin C has also been shown to reduce oxidative stress induced by monosodium glutamate (MSG). In an experimental study on albino rats, vitamin C supplementation protected against degenerative changes in neurons and astrocytes in the cerebellar cortex induced by MSG [154]. Vitamin C also selectively inhibits T-type calcium channels in peripheral and central neurons, which are involved in the control of neuronal excitability [155]. Additionally, vitamin C neutralizes ROS, effectively addressing the oxidative stress caused by excitotoxicity. Therefore, it appears that vitamin C may possess multiple neuroprotective properties.
Despite the limited number of studies concerning the role of vitamin C in migraines, the evidence presented above supports the potential of vitamin C in fighting excitotoxicity, thereby preventing migraines. To date, the only randomized controlled trial related to this research area is a small pilot study that administered N-acetylcysteine, vitamin E, and vitamin C in migraine patients. They showed that this antioxidant combination significantly reduced the frequency, intensity, and duration of attacks, as well as the number of acute medications being used, as compared to the controlled group [156]. Clearly, more research is needed on vitamin C’s efficacy in migraine reduction.
5.5. Vitamin E
Vitamin E is a generic term for compounds called tocopherols and tocotrienols. Alpha-tocopherol is the main form (with the highest biological activity) found in human and animal tissue [157]. Vitamin E has been extensively studied for its antioxidant properties, as the dominant lipid-soluble, chain-breaking antioxidant in the body, which supports membrane integrity by preventing lipid peroxidation [157]. The brain has very high amounts of polyunsaturated fatty acids, making vitamin E essential for the antioxidant protection of these lipids [158].
In an experimental model of neuropathic pain, vitamin E had an analgesic effect by reducing central sensitization [159]. Vitamin E showed potential for fighting excitotoxicity, reducing glial cell activation, neuronal death, neuroinflammation, and oxidative stress in the hippocampus, in an epilepsy model [160,161]. A possible underlying mechanism is attributed to the regulatory effect of vitamin E on glutamine synthase activity, which is believed to be suppressed by oxidative stress [160,162]. Glutamine synthase converts glutamate to glutamine, a non-excitotoxic amino acid, to allow it to be safely shuttled from astrocytes to neurons before being recycled back to glutamate [162]. Vitamin E can also be involved in glutamate and GABA balance through counteracting microglial activation and the inflammatory cascade [163,164]. The cytokines released from microglia affect neuron excitability by modulating astrocytic glutamate receptors and transporters [165]. Substantial evidence from rodent and human studies indicates that inflammation causes downregulation of glutamate decarboxylase activity, which results in a lower conversion of glutamate into GABA, increasing the likelihood of excitotoxicity occurring [166,167,168,169]. In line with this evidence, it was shown that transgenic mice, which express increased levels of pro-inflammatory cytokines or chemokines, had lower levels of glutamate decarboxylase in the hippocampus and cerebellum [170]. Therefore, the anti-inflammatory effects of vitamin E may protect GABA production and vulnerability to more excitation. Furthermore, in vitro evidence has demonstrated that vitamin E reduces astrocytes’ permeability to Ca2+ and Na+ ions by inhibiting protein kinases and downregulating glutamate receptor genes [171].
Vitamin E, as a potential treatment option for migraine, has only been studied in regard to menstrual migraines [172]. A double-blind, placebo-controlled, crossover clinical trial indicated that vitamin E supplementation for five days during two menstrual cycles was associated with significant improvement in pain severity and functional disability [172]. A probable explanation for vitamin E efficacy as a prophylaxis of menstrual migraine is related to its inhibitory effect on phospholipase A2 and cyclooxygenase enzymes. This leads to inhibition of arachidonic acid release from cell membranes and its conversion to prostaglandin [173]. High levels of prostaglandin have been reported in the endometrium during menstruation and in the serum during the premenstrual phase [174]. The inhibitory effect of vitamin E on phospholipase A2 is of substantial value since there is evidence showing that the enzyme targets other intracellular membranes including the mitochondrial membrane as well [175]. Mitochondrial membrane damage is associated with high ROS production, oxidative stress, and ultimately cell death [176]. It is worth noting that antioxidants work together to maintain themselves in an active state, so despite their unique functions in redox balance, they can also be indirectly involved in each other’s activity as well. The benefits described in the aforementioned study looking at the combined effects of vitamin E, vitamin C, and N-acetylcysteine, may have partially been due to these interactive effects of combining antioxidants [156].
5.6. Riboflavin (Vitamin B2)
Riboflavin, also known as vitamin B2, is involved in various metabolic pathways through two coenzyme forms including flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) [177]. In addition to riboflavin’s critical role in energy metabolism, it also has antioxidant function and plays a pivotal role in the metabolism of vitamin B6 (converting dietary pyridoxine into its active form pyridoxal L-phosphate), as well as having roles in DNA repair, and apoptosis [177]. Therefore, deficiency or any disturbance in riboflavin metabolism can contribute to broad-spectrum dysfunction including cardiovascular, neuromuscular, immune, and neurological abnormalities [177].
Riboflavin has direct and indirect ameliorating effects on glutamate excitotoxicity which is implicated in migraine pain. The reduction in voltage-gated Ca2+ channel activity by riboflavin can inhibit endogenous glutamate release by inhibiting glutamate exocytosis in synaptic clefts [178]. In addition, experimental studies demonstrated the neuroprotective effects of riboflavin and pyridoxal phosphate (PLP) on excitotoxicity [179]. As mentioned earlier, riboflavin is involved in the formation of PLP, which is required for the production of many neurotransmitters in the CNS [180]. Very importantly, the conversion of glutamate to GABA, the major inhibitory neurotransmitter in the nervous system, by glutamic acid decarboxylase, necessitates PLP as a cofactor [181]. Therefore, it is not surprising that deficiency in riboflavin and consequent reduction in PLP formation contribute to the elevation of glutamate and reduction in GABA levels, thereby resulting in excitotoxicity. These two vitamins are also crucial for the kynurenine pathway, which is considered the major pathway for the catabolism, or breakdown, of tryptophan [182]. Adequacy of riboflavin and PLP has been linked to the production of kynurenic acid which is a protective antagonist of NMDA and all ionotropic glutamate receptors [183]. Deficiency of these cofactors can lead to further metabolism down the pathway causing the production of quinolinic acid, which is an extremely neurotoxic metabolite that increases the risk of excitotoxicity in multiple ways [184,185].
Riboflavin is one of the most studied vitamins for migraine prophylaxis. In this regard, clinical studies on adult migraine patients have shown very promising results [186,187,188]. A pooled analysis of 8 randomized controlled clinical trials indicated a significant reduction in terms of migraine days, frequency, pain intensity, and duration of attacks following 400 mg/day riboflavin supplementation for three months [189]. Currently, the American Academy of Neurology (level B evidence) recommends 400 mg per day for adult migraineurs [190], as compared to the current recommended dietary allowance of 1.1–1.6 mg per day. It should be noted, that as a water-soluble vitamin, the excess is just being excreted (as can be seen by fluorescent-colored urine when you take riboflavin), and thus, such high doses are likely not needed for benefiting migraine patients. Although not all available evidence is obtained from high-quality trials, due to riboflavin’s low cost, high tolerability, and effectiveness in migraine alleviation in the majority of research, it could be considered an advantageous vitamin for migraine [191].
5.7. Vitamin B6 (Pyridoxine), Folate (Vitamin B9), and Vitamin B12 (Cobalamin)
Vitamins B6, B9, and B12 (in addition to riboflavin) play a key role in one-carbon metabolism, and their deficiency has been linked to elevated levels of homocysteine (Hcy) [192]. Hcy is another neurotoxic metabolite that has the ability to activate NMDA receptors, and vitamins B6, folate, and B12 can protect against its accumulation [192,193].
An experimental model of pain induced by acetic acid demonstrated the antinociceptive effects of B vitamins [194]. However, it seems the effectiveness of these vitamins in migraine prophylaxis could be attributed to their effect on lowering Hcy for the most part. Notably, the role of riboflavin in the production of the active form of pyridoxine makes it indirectly involved in this pathway as well [192]. The presence of high levels of Hcy in the brain might act as a trigger or amplifier in a variety of ways [195]. Hcy has a known neurotoxic effect via direct stimulation of NMDA receptors and consequent excitotoxicity [193]. Previously, it has also been shown that Hcy acts as an antagonist to GABA-A receptors, influencing the migraine pain threshold negatively [196]. Homocysteine also contributes to the breakdown of the extracellular matrix which affects BBB integrity [196]. An increase in brain microvascular permeability was also observed in mice with hyperhomocysteinemia via the activation of matrix metalloproteinases, which lead to vascular remodeling and BBB disruption [197].
Migraine, especially migraine with aura, is associated with a risk of ischemic stroke [198], and elevated levels of Hcy in migraineurs have been identified as a potential risk factor for stroke, as reported by epidemiological studies [199,200]. Evidence showing the effectiveness of B6, B9, and B12 vitamins on Hcy level reduction encouraged trials to explore the beneficial effects of Hcy-lowering vitamins. In a double-blind randomized controlled trial by Askari et al., 3 months of supplementation with folic acid plus pyridoxine in migraine patients with aura, led to significant improvement in migraine characteristics compared to placebo [201]; while in the migraine group that received folic acid alone, no significant change was detected in comparison with the placebo group [201]. One clinical trial tested pyridoxine supplementation for migraine patients with aura, and the authors reported a reduction in the severity and duration of attacks, but no effects on the frequency of attacks were noted [202].
5.8. Coenzyme Q10 (CoQ10)
CoQ10 is a fat-soluble compound mostly found in animal proteins, but also in beans, nuts, seeds, and avocado [203]. Our body can synthesize CoQ10, thus its dietary intake is not considered essential. However, evidence has shown that CoQ10 deficiency can occur secondary to several mitochondrial disorders, aging, and in those using statins (for lowering cholesterol) [204,205]. As mentioned before, migraine patients are prone to mitochondrial dysfunction as a result of excitotoxicity-mediated oxidative stress. CoQ10 plays a key role in energy production in mitochondria and also acts as an antioxidant in cell membranes [203]. Interestingly, it is involved in the restoration of the oxidized form of vitamin E, helping to restore vitamin E’s antioxidant function [206].
Preclinical evidence supports the protective effect of CoQ10 against excitotoxicity. In a mouse model of glaucoma, a diet supplemented with CoQ10 ameliorated glutamate excitotoxicity and oxidative stress compared to an un-supplemented control diet [207]. In another study, the effect of CoQ10 on the endogenous release of glutamate in the cerebral cortex was evaluated [208]. The findings suggested that CoQ10 inhibited glutamate release from cortical synaptosomes in rats via suppression of the presynaptic voltage-dependent Ca2+ channels and extracellular signal-regulated kinase pathway. Water-soluble CoQ10 (Ubisol-Q10) has also been shown to reduce glutamate-induced cell death in an in vitro model [209]. Murine hippocampal neuronal cells were exposed to glutamate, 24 h after Ubisol-Q10 treatment. The results indicated that CoQ10 protects the neuronal cells by preserving mitochondrial function and structure.
The beneficial impact of CoQ10 supplementation on migraine-related outcomes has been tested in several clinical studies [210,211,212,213]. The pooled result of the most recent meta-analysis of 6 studies supports the idea that CoQ10 supplementation can reduce the frequency and duration of migraine attacks but does not reduce severity [214].
6. Gap between Pathophysiology of Migraine and Interventions: Where Do We Stand Now?
The contribution of glutamate to neuropathological aspects of migraine has led to the development of several glutamate antagonists as migraine prophylactic drugs [215,216,217,218]. However, these drugs have limited utility and a high probability of side effects [219,220].
Clinical trials in migraineurs have provided supportive findings for all reviewed nutrients including riboflavin, folate, pyridoxine, cobalamin, vitamin D, C, E, magnesium, and omega-3 fatty acids. These nutrients have shown potential for alleviating excitotoxicity as well. Given the evidence indicating nutrient deficiency among migraineurs [148,200,221], replenishment of these nutrients seems reasonable. However, dietary nutrients are often studied one at a time, which inhibits potential synergism and cooperative effects between nutrients from being observed. Thus, applying a more comprehensive dietary approach may yield greater results.
Notably, besides being an endogenous source, glutamate is a non-essential amino acid found in the diet [222]. In a normal situation, the amount of dietary glutamate entering the brain is regulated by saturable transporters on the BBB [223]. However, considering the probability of diminished BBB integrity in migraine patients [224,225,226,227,228], it is likely that the amount of dietary glutamate entering the brain is higher than in healthy individuals. This idea is supported by multiple studies that have shown that MSG administration can induce headaches [229,230,231]. Moreover, some dietary components could have a triggering effect on a migraine attack as reported by patients in epidemiological studies [232,233]. The contribution of dietary triggers in migraines was the basis for the development of elimination diet strategies [234]. However, precisely determining random food triggers is challenging, and a diet that is overly restrictive can have a long-term negative effect on nutritional status [235,236]. Until now, no specific diet has been developed for migraine prevention, and several proposed diets have shown varying levels of efficacy [237]. Taken together, both dietary triggers and nutrient intake might be key to therapeutic benefits in migraine, which has not been possible with current interventions.
Our team previously administered a diet-based intervention called the “low glutamate diet” in patients with widespread chronic pain disorders [222,238,239]. This diet removes free forms (i.e., not bound to a protein) of glutamate and aspartate (mainly by restricting food additives with excitotoxins, in addition to a few foods that are naturally high in glutamate/aspartate such as soy sauce, fish sauce, and aged cheeses), while also emphasizing the intake of foods high in the micronutrients reviewed above [238]. This diet has shown benefits for widespread chronic pain conditions [222,240], including Gulf War illness (GWI) [238]. Interestingly, all of these studies have demonstrated widespread symptom improvement, including reduced reports of migraines. Figure 3 illustrates the significant reduction in migraine in veterans with Gulf War Illness after one month on the diet. Moreover, most subjects reported going from multiple weekly migraines to no migraines during the diet month. We believe these symptom improvements in patients suffering from widespread chronic pain disorders stem from reductions in central sensitization (from reduced excitotoxicity) and potentially corresponding improvements in the inter-related occurrence of oxidative stress and neuroinflammation. More in-depth research is warranted to further explore whether or not the low glutamate diet may be used as an effective treatment for migraine.
Figure 3. Change in percentage of subjects with Gulf War Illness (n = 40) reporting migraine before and after one month on the low glutamate diet. Chi-square significance of p = 0.04.
7. Conclusions
Glutamate-mediated excitotoxicity is associated with a wide range of neurological disorders including migraine. The proposed mechanisms include the direct effect of excitotoxicity on neuronal injury or death, or its contribution to neuroinflammation, oxidative stress, blood-brain barrier permeability, and cerebral vasodilation, all of which are associated with migraine pathophysiology. Available evidence supports the role of several nutrients in protecting against excitotoxicity including riboflavin, folate, pyridoxine (vitamin B6), cobalamin (vitamin B12), vitamin D, C, E, magnesium, and omega-3 fatty acids. Additional evidence also suggests that supporting endogenous production of CoQ10 with increased dietary intake may also be protective. Interestingly, clinical data support the role of these nutrients in improving migraines as well, providing a strong rationale for designing effective interventions. There is an obvious gap between our understanding of migraines and the dietary strategies which have been administered so far, since dietary nutrients are often studied separately, and no specific diet for migraine has been developed. However, the beneficial effects of the low glutamate diet on widespread chronic pain disorders appear to have overlapping mechanistic effects, and additionally is some preliminary evidence supporting an effect on migraine. Thus, further research on this dietary strategy in migraine is warranted.