Research progress on oxidative stress regulating different types of neuronal death caused by epileptic seizures

Sun, Haogang; Li, Xinxin; Guo, Qi; Liu, Songyan

doi:10.1007/s10072-022-06302-6

Cited by 18 publications

(12 citation statements)

References 224 publications

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Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that not only dysregulation of the endogenous antioxidant system, but also mitochondrial dysfunction contribute to oxidative burdens in the hippocampus following seizures induced by excitotoxins, including KA. 14,97 Melatonin have been reported to attenuate KA-induced mitochondrial dysfunction. 50,98 Previously, we also reported that melatonin restores mitochondrial function and attenuates mitochondrial oxidative stress in dopaminergic neurotoxic conditions induced by methamphetamine.…”

Section: Discussionmentioning

confidence: 99%

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Ramelteon attenuates hippocampal neuronal loss and memory impairment following kainate‐induced seizures

Park,

Hwang,

Nguyen

et al. 2023

Journal of Pineal Research

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Evidence suggests that the neuroprotective effects of melatonin involve both receptor‐dependent and ‐independent actions. However, little is known about the effects of melatonin receptor activation on the kainate (KA) neurotoxicity. This study examined the effects of repeated post‐KA treatment with ramelteon, a selective agonist of melatonin receptors, on neuronal loss, cognitive impairment, and depression‐like behaviors following KA‐induced seizures. The expression of melatonin receptors decreased in neurons, whereas it was induced in astrocytes 3 and 7 days after seizures elicited by KA (0.12 μg/μL) in the hippocampus of mice. Ramelteon (3 or 10 mg/kg, i.p.) and melatonin (10 mg/kg, i.p.) mitigated KA‐induced oxidative stress and impairment of glutathione homeostasis and promoted the nuclear translocation and DNA binding activity of Nrf2 in the hippocampus after KA treatment. Ramelteon and melatonin also attenuated microglial activation but did not significantly affect astroglial activation induced by KA, despite the astroglial induction of melatonin receptors after KA treatment. However, ramelteon attenuated KA‐induced proinflammatory phenotypic changes in astrocytes. Considering the reciprocal regulation of astroglial and microglial activation, these results suggest ramelteon inhibits microglial activation by regulating astrocyte phenotypic changes. These effects were accompanied by the attenuation of the nuclear translocation and DNA binding activity of nuclear factor κB (NFκB) induced by KA. Consequently, ramelteon attenuated the KA‐induced hippocampal neuronal loss, memory impairment, and depression‐like behaviors; the effects were comparable to those of melatonin. These results suggest that ramelteon‐mediated activation of melatonin receptors provides neuroprotection against KA‐induced neurotoxicity in the mouse hippocampus by activating Nrf2 signaling to attenuate oxidative stress and restore glutathione homeostasis and by inhibiting NFκB signaling to attenuate neuroinflammatory changes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ramelteon attenuates hippocampal neuronal loss and memory impairment following kainate‐induced seizures

Park,

Hwang,

Nguyen

et al. 2023

Journal of Pineal Research

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“…Clinical and experimental data indicate that prolonged and recurrent epileptic seizures can lead to chronic brain damage and neuronal death. Oxidative stress plays a critical role in various forms of neuronal death caused by epileptic seizures [72]. Pentylenetetrazole kindling is a well-established animal model that simulates clinical epilepsy.…”

Section: Neuroprotective Properties Of Thymoquinone In Modeling Epilepsymentioning

confidence: 99%

Antioxidant Thymoquinone and Its Potential in the Treatment of Neurological Diseases

2023

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Oxidative stress is one of the main pathogenic factors of neuron damage in neurodegenerative processes; this makes it an important therapeutic target to which the action of neuroprotectors should be directed. One of these drugs is thymoquinone. According to modern data, this substance has a wide range of pharmacological activity, including neuroprotective, which was demonstrated in experimental modeling of various neurodegenerative diseases and pathological conditions of the brain. The neuroprotective effect of thymoquinone is largely due to its antioxidant ability. Currently available data show that thymoquinone is an effective means to reduce the negative consequences of acute and chronic forms of cerebral pathology, leading to the normalization of the content of antioxidant enzymes and preventing an increase in the level of lipid peroxidation products. Antioxidant properties make this substance a promising basis for the development of prototypes of therapeutic agents aimed at the treatment of a number of degenerative diseases of the central nervous system.

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Section: Introductionmentioning

confidence: 99%

“…Epilepsy is a neurological disorder characterized by recurrent and spontaneous seizures (Christensen et al, 2023); when left uncontrolled, it can lead to neuronal damage (Sun et al, 2022), cognitive deficits (Chai et al, 2023), and even sudden unexpected death (SUDEP) (Whitney et al, 2023). A prominent feature of epileptic seizures is hyperexcitability and excessive abnormal neural activity, which in some cases could be attributed to genetic changes in ion channels (Oyrer et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Human iPSC-derived microglia sense and dampen hyperexcitability of cortical neurons carrying the epilepsy-associated SCN2A-L1342P mutation

Que,

Olivero-Acosta,

Chen

et al. 2023

Preprint

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Neuronal hyperexcitability is a hallmark of seizures. It has been recently shown in rodent models of seizures that microglia, the brain’s resident immune cells, can respond to and modulate neuronal excitability. However, how human microglia interacts with human neurons to regulate hyperexcitability mediated by epilepsy-causing genetic mutation found in human patients remains unknown. TheSCN2Agenetic locus is responsible for encoding the voltage-gated sodium channel Nav1.2, recognized as one of the leading contributors to monogenic epilepsies. Previously, we demonstrated that the recurring Nav1.2-L1342P mutation identified in patients with epilepsy leads to hyperexcitability in a hiPSC-derived cortical neuron model from a male donor. While microglia play an important role in the brain, these cells originate from a different lineage (yolk sac) and thus are not naturally present in hiPSCs-derived neuronal culture. To study how microglia respond to diseased neurons and influence neuronal excitability, we established a co-culture model comprising hiPSC-derived neurons and microglia. We found that microglia display altered morphology with increased branch length and enhanced calcium signal when co-cultured with neurons carrying the Nav1.2-L1342P mutation. Moreover, the presence of microglia significantly lowers the action potential firing of neurons carrying the mutation. Interestingly, we further demonstrated that the current density of sodium channels in neurons carrying the epilepsy-associated mutation was reduced in the presence of microglia. Taken together, our work reveals a critical role of human iPSCs-derived microglia in sensing and dampening hyperexcitability mediated by an epilepsy-causing mutation present in human neurons, highlighting the importance of neuron-microglia interactions in human pathophysiology.Significance StatementSeizure studies in mouse models have highlighted the role of microglia in modulating neuronal activity, particularly in the promotion or suppression of seizures. However, a gap persists in comprehending the influence of human microglia on intrinsically hyperexcitable neurons carrying epilepsy-associated pathogenic mutations. This research addresses this gap by investigating human microglia and their impact on neuronal functions. Our findings demonstrate that microglia exhibit dynamic morphological alterations and calcium fluctuations in the presence of neurons carrying an epilepsy-associated SCN2A mutation. Furthermore, microglia suppressed the excitability of diseased hyperexcitable neurons, suggesting a potential beneficial role. This study underscores the role of microglia in the regulation of abnormal neuronal activity, providing insights into therapeutic strategies for neurological conditions associated with hyperexcitability.

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Research progress on oxidative stress regulating different types of neuronal death caused by epileptic seizures

Cited by 18 publications

References 224 publications

Ramelteon attenuates hippocampal neuronal loss and memory impairment following kainate‐induced seizures

Ramelteon attenuates hippocampal neuronal loss and memory impairment following kainate‐induced seizures

Antioxidant Thymoquinone and Its Potential in the Treatment of Neurological Diseases

Human iPSC-derived microglia sense and dampen hyperexcitability of cortical neurons carrying the epilepsy-associated SCN2A-L1342P mutation

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