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https://www.mdpi.com/2072-6643/10/6/730

Deciphering the role of metal and non-metals in the treatment of epilepsy

Author links open overlay panelRuksar Sande, Gaurav Doshi, Angel Godad

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Abstract

Metals and non-metals have known to play a significant role in various physiological roles in the body including the central nervous system (CNS). The alterations in their concentration in the CNS leads to abnormalities in the normal functions which may lead to various neurological conditions including epilepsy. Manganese is a cofactor required for antioxidant enzymes such as Superoxide dismutase, Glutamine synthetase, etc. The accumulation of iron leads to formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) which have the potential to cause ferroptosis, one of the reasons for epileptogenesis. Zinc has biphasic response, both neurotoxic and neuroprotective, based on concentration levels in the CNS. Selenium is a main element for selenoproteins which is responsible for the regulation of oxidative state and antioxidant defence mechanism. The reduction in the phosphorous levels in the CNS is widely observed after generalised tonic clonic seizures (GTC), which can be a potential diagnostic biomarker. Copper acts in the CNS in an identical manner, i.e., by blocking both AMPA mediated and GABA mediated neuronal transmission. Magnesium blocks calcium channels in the NMDA receptor and prevents glutamatergic transmission, thus inhibiting excitotoxicity. Lithium acts as a proconvulsive agent and is used in combination with pilocarpine to induce seizures. The identified potential of metals and non-metals in epilepsy can be utilised in order to devise new adjuvant therapies for the management of epilepsy. The article summaries in depth the role of metals and non-metals in the treatment of epilepsy supported with special paragraph on author perspective on to the topic. Furthermore, an update of preclinical and clinical evidences are discussed in the review to give evidence on metal and non-metal based therapies in epilepsy.

금속과 비금속은 중추신경계(CNS)를 포함한 신체의 다양한 생리적 역할에 중요한 역할을 하는 것으로 알려져 있습니다. 중추신경계의 농도가 변화하면 정상적인 기능에 이상이 생겨 간질을 비롯한 다양한 신경 질환을 유발할 수 있습니다. 

망간은 

슈퍼옥사이드 디스뮤타제, 글루타민 합성 효소 등과 같은 

항산화 효소에 필요한 보조 인자입니다. 

철분이 축적되면 

활성 산소종(ROS)과 활성 질소종(RNS)이 형성되어 

간질 발생의 원인 중 하나인 페로셉토시스를 유발할 가능성이 있습니다. 

아연은 

중추신경계의 농도에 따라 신경 독성과 

신경 보호라는 양상 반응을 보입니다. 

셀레늄은 

산화 상태의 조절과 항산화 방어 메커니즘을 담당하는 

셀레노 단백질의 주요 원소입니다. 

중추신경계에서 인 수치의 감소는 

전신성 긴장성 간대성 발작(GTC) 후에 널리 관찰되며, 

이는 잠재적인 진단 바이오마커가 될 수 있습니다. 

구리는 동일한 방식으로, 

즉 AMPA 매개 신경 전달과 GABA 매개 신경 전달을 모두 차단하는 방식으로 

CNS에서 작용합니다. 

마그네슘은 

NMDA 수용체의 칼슘 채널을 차단하고 

글루탐산 전달을 방지하여 흥분성 독성을 억제합니다. 

리튬은 

항경련제 역할을 하며 필로카핀과 함께 발작을 유도하는 데 사용됩니다. 

뇌전증에서 

금속과 비금속의 잠재력을 확인한 것은 

뇌전증 관리를 위한 새로운 보조 요법을 고안하는 데 활용될 수 있습니다. 

이 논문은 뇌전증 치료에서 금속과 비금속의 역할을 심도 있게 요약하고 있으며, 이 주제에 대한 저자의 관점을 담은 특별 단락을 통해 이를 뒷받침하고 있습니다. 또한, 전임상 및 임상 증거의 업데이트에 대해 논의하여 뇌전증에서 금속 및 비금속 기반 치료법에 대한 근거를 제시합니다.

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Role of metal and non-metals in the treatment of epilepsy.

Introduction

Epilepsy is a neurological disorder characterised by spontaneously occurring seizures which can either be localised or widespread across the brain (Steriade et al., 2020). The main cause for the occurrence of seizures is the imbalance between the inhibitory neurotransmitter Gamma amino Butyric Acid (GABA) and excitatory neurotransmitter Glutamate (Green et al., 2021). The levels of GABA are significantly reduced while that of the glutamate are prominently increased leading to the excessive neuronal firing causing seizures, ultimately leading to epilepsy (Treiman, 2001). Around 1% of the total Indian population and 1.25 of the total U.S population is affected by epilepsy (Kambli et al., 2017; Pitkänen et al., 2016). Globally, an estimated 5 million people are diagnosed with epilepsy each year (Aneja and Sharma, 2013). Numerous classes of anti-epileptic drugs are available in the market. Sodium channel, glutamate and calcium channel blockers, GABA receptor agonists, GABA transaminase and GABA reuptake inhibitors, are well-established anti-epileptic category drugs (Aneja and Sharma, 2013).

뇌전증은 자발적으로 발생하는 발작을 특징으로 하는 신경학적 장애로, 국소적이거나 뇌 전체에 걸쳐 광범위하게 발생할 수 있습니다(스테리아데 외., 2020). 

발작 발생의 주요 원인은 

억제성 신경전달물질인 감마 아미노 부티르산(GABA)과 

흥분성 신경전달물질인 글루타메이트 사이의 불균형입니다(Green et al., 2021). 

GABA 수치는 현저히 감소하는 반면 

글루타메이트 수치는 눈에 띄게 증가하여 

발작을 유발하는 과도한 신경 세포 발화로 이어져 궁극적으로 간질을 유발합니다 (Treiman, 2001). 

인도 전체 인구의 약 1%, 미국 전체 인구의 1.25%가 뇌전증의 영향을 받고 있습니다(Kambli et al., 2017; Pitkänen et al., 2016). 전 세계적으로 매년 약 5백만 명이 뇌전증 진단을 받습니다(Aneja and Sharma, 2013). 수많은 종류의 항전간제가 시중에 나와 있습니다. 

나트륨 채널, 

글루타메이트 및 칼슘 채널 차단제, 

가바 수용체 작용제, 

가바 트랜스아미나제 및 가바 재흡수 억제제는 잘 알려진 항전간제 범주 약물입니다(Aneja and Sharma, 2013).

Metals and some non-metals are essential for intra and inter neuronal signalling as well as serving as enzyme cofactors (Kim et al., 2022). The disturbances in their concentration in the brain are often associated with neurological condition including Alzheimer's disease, Parkinson's disease, Depression and Epilepsy (Chen et al., 2016a; Chung et al., 1986). Over the past few decades, several reports suggest the involvement of various metal and non-metals including copper, iron, manganese, zinc, selenium, phosphorus and magnesium in either the progression or suppression of epilepsy (Chen et al., 2016a; Chung et al., 1986; Saghazadeh et al., 2015). Manganese at normal levels acts as an antioxidant in the brain by combining with manganese dependent enzymes such as Manganese Superoxide Dismutase (MnSOD), Arginase, Agmatinase and Glutamine synthetase (Kim et al., 2022; Takeda, 2003a; Grant, 2004). Iron is an essential metal in the cytochrome, cytochrome oxidases and iron sulfur complexes and acts as a cofactor for enzymes such as Tryptophan hydroxylase and Tyrosine Hydroxylase (Abbaspour et al., 2014).

금속과 일부 비금속은 

신경세포 내 및 신경세포 간 신호 전달에 필수적이며 

효소 보조인자로도 작용합니다(Kim et al., 2022). 

뇌에서의 농도 교란은 종종 

알츠하이머병, 파킨슨병, 우울증 및 간질과 같은 

신경학적 상태와 관련이 있습니다(Chen et al., 2016a; Chung et al., 1986). 

지난 수십 년 동안 

구리, 철, 망간, 아연, 셀레늄, 인, 마그네슘을 포함한 

다양한 금속 및 비금속이 간질의 진행 또는 억제에 관여한다는 여러 보고서가 발표되었습니다

(Chen et al., 2016a; Chung et al., 1986; Saghazadeh et al., 2015). 

정상 수준의 망간은 

망간 슈퍼옥사이드 디스뮤타제(MnSOD), 아르기나제, 아그마티나제, 글루타민 합성효소 등 

망간 의존성 효소와 결합하여 

뇌에서 항산화제로 작용합니다(Kim et al., 2022; Takeda, 2003a; Grant, 2004). 

철은 

시토크롬, 시토크롬 산화 효소 및 철 황 복합체의 필수 금속이며 

트립토판 하이드 록실 라제 및 티로신 하이드 록실 라제와 같은 

효소의 보조 인자로 작용합니다 (Abbaspour et al., 2014).

However, excessive iron accumulation is associated with the free radical generation which can further contribute in the progression of epilepsy (Chen et al., 2020a). Zinc has been found to demonstrate both pro as well as anti-convulsant effects, dose dependently (Doboszewska et al., 2019). At high doses zinc may prove to be neurotoxic, while at moderate levels, zinc has shown to synergise anti-epileptic potential of conventional drugs in animal models (Barbeau and Donaldson, 1974). Selenium exerts neuroprotective effect by regulation of oxidative state and in antioxidant defence (Nazıroğlu, 2009a). The deficiency of phosphorous, i.e., hypophosphatemia was the most common recognised pattern in epileptic patients.

그러나

과도한 철분 축적은

자유 라디칼 생성과 관련이 있으며,

이는 간질 진행에 더욱 기여할 수 있습니다(Chen et al., 2020a). 

아연은 

용량에 따라 항경련 효과와 

항경련 효과를 모두 나타내는 것으로 밝혀졌습니다(Doboszewska et al., 2019). 

고용량에서는 아연이 신경 독성을 나타낼 수 있지만, 

중간 수준에서는 아연이 동물 모델에서 기존 약물의 항간질 잠재력을 상승시키는 것으로 나타났습니다(Barbeau and Donaldson, 1974). 

셀레늄은 

산화 상태의 조절과 항산화 방어를 통해 

신경 보호 효과를 발휘합니다(Nazıroğlu, 2009a). 

인의 결핍, 즉 

저인산혈증은 

간질 환자에서 가장 흔하게 인식되는 패턴이었습니다.

However, it was also estimated that deficiency of phosphorous was more of a consequence than a cause, and hence can be a potential diagnostic tool (Barras et al., 2019a). A crucial element, copper, is known to modulate neurotransmission via a biphasic mechanism, exhibiting action on neuropathology and neurobiology of the CNS (Talat et al., 2015a). Magnesium acts a blocker for calcium channel in the NMDA receptor, thus inhibiting the excitotoxicity (Dhande et al., 2009a). Lithium acts as a proconvulsive agent and is used in combination with pilocarpine to potentiate its effect (Julius and Brenner, 1987). Despite several preclinical and clinical studies conducted in regard with the role of metals and non-metals in epilepsy, further investigations are anticipated for the better understanding of the more detailed mechanism of metals and non-metals in either progression or suppression of epilepsy (Saghazadeh et al., 2015). This review emphasizes on the significance of metals and non-metals in epilepsy based on the preclinical and clinical evidences.

그러나 

인 결핍은 

원인보다는 결과에 가깝기 때문에 

잠재적인 진단 도구가 될 수 있다고 추정되었습니다(Barras et al., 2019a). 

중요한 원소인 구리는 

중추신경계의 신경병리 및 신경생물학에 작용하여 

2상 메커니즘을 통해 신경전달을 조절하는 것으로 알려져 있습니다(Talat et al., 2015a). 

마그네슘은 

NMDA 수용체에서 칼슘 채널의 차단제로 작용하여 

흥분 독성을 억제합니다(Dhande et al., 2009a). 

리튬은 

항경련제로 작용하며 필로카핀과 함께 사용하여 그 효과를 강화합니다(Julius and Brenner, 1987). 

간질에서 금속과 비금속의 역할과 관련하여 여러 전임상 및 임상 연구가 수행되었지만, 간질의 진행 또는 억제에서 금속과 비금속의 보다 자세한 메커니즘을 더 잘 이해하기 위해서는 추가 조사가 필요할 것으로 예상됩니다(Saghazadeh et al., 2015). 이 리뷰는 전임상 및 임상 증거를 바탕으로 간질에서 금속과 비금속의 중요성에 대해 강조합니다.

Section snippets

Manganese and epilepsy

Due to its function in the activity of several metalloprotein enzymes, manganese, a required micronutrient for humans, is a trace element important for numerous physiological functions (Akram et al., 1989). A deficiency of this crucial element might result in cognitive deficiencies. Humans typically have blood levels between 4.2 and 16.5 μg/L, serum levels between 0.40 and 0.85 μg/L, and brain levels between 1 and 2 μg/g dry weight (Aschner, 2006; Jankovic, 2005). Substantial pathogenic

여러 금속 단백질 효소의 활성에 관여하는 기능으로 인해 

인간에게 필수 미량 영양소인 망간은 

수많은 생리적 기능에 중요한 미량 원소입니다(Akram et al., 1989). 

이 중요한 원소가 결핍되면 

인지 기능에 결함이 생길 수 있습니다. 

일반적으로 사람의 혈중 농도는 4.2~16.5μg/L, 

혈청 농도는 0.40~0.85μg/L, 

뇌 농도는 1~2μg/g입니다(Aschner, 2006; Jankovic, 2005). 

Iron and epilepsy

Iron is a constituent of many proteins, including enzymes and haemoglobin, which is necessary for supplying oxygen to all body tissues for metabolism (Lieu et al., 2001a, 2001b). Due to its high energy requirements, the brain has a reasonably high need for iron. Maintaining the membrane ionic gradients, synaptic transmission, and axonal transport—all of which are very active processes in the brain—requires adenosine triphosphate (ATPs). Iron is important for the synthesis of ATP because it is

Zinc and epilepsy

Although the body only needs trace amounts of zinc, nearly 100 enzymes depend on it to carry out crucial chemical reactions. Zinc is essential for stem cell proliferation and differentiation throughout neurodevelopment and formation and effective functioning of a number of proteins, enzymes, hormones, and growth factors (Sandstead et al., 1967; Zinc and its importance for, 2023). The majority of the zinc in the CNS is strongly connected to transcription factor proteins, metallothioneins, and

Selenium and epilepsy

As a by-product of the synthesis of sulphuric, the non-metal trace element known as selenium was discovered in 1817. Studies have discovered that white matter has lower Selenium levels than the parts of the human brain that are abundant in grey matter (Arbogast and Ferreiro, 2010). The hippocampus, cerebellum, brainstem, and ventricles of the rat brain exhibited the highest levels of selenium, according to Kuhbacher et al. Selenoproteins were demonstrated to be mostly expressed in brain cells

Phosphorous in epilepsy

An element termed phosphorus is found in many foods naturally and can also be taken as a supplement. The role of phosphorous in the CNS has been suggested according to recent studies (Recent findings in phosphate metabolism, 2023). The most frequent electrolyte abnormality, seen in every second GTC seizure and far less frequently in other transient loss of consciousness (TLOC) causes, was hypophosphatemia. Although disturbance of plasma phosphate levels is not widely believed as a cause of

Copper and epilepsy

Copper is vital for living systems, however may even prove to be toxic. It has regulatory and signalling roles in a variety of biological processes, in addition to its well-known function as an enzyme cofactor. Copper affects synaptic transmission via modifying the actions of GABAA and NMDA receptors as well as voltage-gated Ca2+ channels, which are both necessary for the myelination of neurons (Sharonova et al., 1998). Changes in copper concentrations modify glycolytic flux of astrocytes and

Magnesium and epilepsy

Magnesium is a mineral that occurs naturally in a wide variety of foods, is a supplement, and is a key ingredient in antacids and laxatives. It performs a variety of crucial brain activities as a result of its interaction with the NMDA receptor. Magnesium inhibits the calcium channel in the NMDA receptor and must be eliminated for glutamatergic excitatory transmission to take place. Lower magnesium levels may induce excitotoxicity and glutamatergic neurotransmission, which can result in

Lithium and epilepsy

An element that occurs naturally called lithium remains to be the gold standard drug for the treatment of bipolar disorders. Because a significant percentage of epileptic patients experience psychiatric comorbidities like anxiety, depression, postictal mania, psychosis, and other mood disorders, the function of lithium in managing epilepsy is of vital importance (Julius and Brenner, 1987; Wharton, 1969; Schmitz, 2005). Mania can also develop as a side effect of anti-epileptic medications such

Iron based treatment approaches

Ferroptosis is activated by a range of neurological conditions, including epilepsy (Chen et al., 2020b). Studies conducted recently have demonstrated the delaying the development and progression of epilepsy by lowering nerve damage caused by ferroptosis and iron metabolism (Chen et al., 2020a; Kahn-Kirby et al., 2019). It is hypothesized that inhibiting ferroptosis can help prevent epileptic episodes since ferroptosis has been identified as one of the contributing elements to the formation of

Author's insights and perspective to the topic

Metals as well as few non-metals are known to play a key role in maintaining the homeostasis as well as appropriate regulation of the bodily functions. Similarly, both metals and non-metals are known to contribute in the normal physiology and functioning of the CNS. The irregularities in their concentrations are often associated with certain disorders. In case of CNS, these metal/non-metal imbalances are associated with various neurological disorders. Epilepsy, a disorder based on

Conclusion

Metals and non-metals have significant roles in various functions of the body, including CNS. The abnormalities in the metal/non-metal concentrations in the CNS are often associated with various neurological conditions including epilepsy. However, extensive studies are required to decode the detailed mechanism in regard with the role of metals/non-metals in epilepsy. Further, supplements as well as newer agents affecting the metal/non-metal concentration should be clinically investigated so as

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author's contributions

Ms. Ruksar Sande, Dr. Gaurav Doshi and Mr. Angel Godad contributed in the form of conceptualization and drafting of the manuscript. Dr. Gaurav Doshi, and Mr. Angel Godad contributed in the form of redefining conceptualization and finalizing the manuscript draft written by Ms. Ruksar Sande.

Declaration of competing interest

The authors declare no conflict of interest.

Acknowledgements

None.

References (180)

• M. Aschner
• G. Barbella et al.Hypophosphatemia compared to classical biomarkers of tonic clonic seizures
• O. Devinsky et al.Glia and epilepsy: excitability and inflammation
• U. Doboszewska et al.Zinc signaling and epilepsy
• V.A. Fitsanakis et al.The effects of manganese on glutamate, dopamine and γ-aminobutyric acid regulation
• M. Fukahori et al.Effects of dietary zinc status on seizure susceptibility and hippocampal zinc content in theEl (epilepsy) mouse
• S.A. Hamed et al.Blood levels of trace elements, electrolytes, and oxidative stress/antioxidant systems in epileptic patients