Ferroptosis and Its Role in Epilepsy

Cai, Yuxiang; Yang, Zhiquan

doi:10.3389/fncel.2021.696889

Cited by 53 publications

(38 citation statements)

References 94 publications

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“…Because of the lack of effective treatment, sequelae caused by neurological disorders have brought an enormous burden on society. Ferroptosis has been proved to be closely related to the occurrence and development of various neurological disorders [40][41][42][43]. Therefore, figuring out the role of ferroptosis in neurological disorders will provide an important basis for the treatment of diseases (Figure 1, Table 1).…”

Section: Ferroptosis In Neurological Disordersmentioning

confidence: 99%

Targeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders

Jia

Cheng

et al. 2022

Oxidative Medicine and Cellular Longevity

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With the acceleration of population aging, nervous system diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), anxiety, depression, stroke, and traumatic brain injury (TBI) have become a huge burden on families and society. The mechanism of neurological disorders is complex, which also lacks effective treatment, so relevant research is required to solve these problems urgently. Given that oxidative stress-induced lipid peroxidation eventually leads to ferroptosis, both oxidative stress and ferroptosis are important mechanisms causing neurological disorders, targeting mediators of oxidative stress and ferroptosis have become a hot research direction at present. Our review provides a current view of the mechanisms underlying ferroptosis and oxidative stress participate in neurological disorders, the potential application of molecular mediators targeting ferroptosis and oxidative stress in neurological disorders. The target of molecular mediators or agents of oxidative stress and ferroptosis associated with neurological disorders, such as reactive oxygen species (ROS), nuclear factor erythroid 2–related factor-antioxidant response element (Nrf2-ARE), n-acetylcysteine (NAC), Fe2+, NADPH, and its oxidases NOX, has been described in this article. Given that oxidative stress-induced ferroptosis plays a pivotal role in neurological disorders, further research on the mechanisms of ferroptosis caused by oxidative stress will help provide new targets for the treatment of neurological disorders.

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Section: Ferroptosis In Neurological Disordersmentioning

confidence: 99%

Targeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders

Jia

Cheng

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Recent studies showed that the ferroptosis was not only related to chronic central nervous system diseases such as Alzheimer's disease, stroke, Parkinson's disease and Huntington's disease, but also palied a crucial role in epilepsy [20] . Recent study showed that inhibition of ferroptosis could alleviate the symptoms and improve the prognosis of epileptic seizures.…”

Section: Discussionmentioning

confidence: 99%

Chloroquine exerts antiepileptic and neuroprotective effects through the P62-Keap1-Nrf2-GPX4-ferroptosis pathway in pentatetrazone-induced epileptic rat model

Zhang

et al. 2022

Preprint

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Background: Epilepsy is one of the most common brain disease. Increasing studies have revealed that ferroptosis plays a significant role in the development of epilepsy. Choloroquine(CQ) can release P62 by inhibiting the fusion of autophagosomes with lysomes in the process of autophagy. Our study aimed at investigating the antiepileptic and neuroprotective benefits of CQ via the P62-Keap1-Nrf2-GPX4-ferroptosis pathway in epilepic rats and illustrating the possible connection between autophagy and ferroptosis preliminarily. Methods: 45 male SD rats were randomly divided into three groups: control, pentylenetetrazol(PTZ; 35mg/kg), CQ(40mg/kg)+PTZ groups, all the rats were injected 15 times every other day in a total of 29 days. The EEG changes and behavioral manifestations(epileptic score, latency, and number of seizures in 30 minutes) were recorded. Patch clamp technique was applied to evaluating the excitability of hippocampal neurons. Nissl staining was utilized to observe the neurons in hippocampus. Spectrophotometry was used to evaluate the expression levels in hippocampus of Fe2+, glutathione(GSH) and malondialdehyde(MDA). The expression of P62, LC3, Keap1, Nrf2, GPX4 and PTGS2 was determined by Immunohistochemistry and Western-blot. Results: CQ intervention reduced the level and number of seizures, as well as the latency of seizures, in the PTZ-induced epileptic model. Furthermore, as compared to the PTZ group, CQ reduced the excitability of hippocampus neurons according to patch clamp technique. And the number of pathological neurons in the hippocampal CA1 region decreased based on nissl staining. CQ therapy also prevented MDA and iron accumulation while increasing the expression of GSH, according to spectrophotometry..The expression of P62, LC3, Nrf2, GPX4 increased significantly and the level of Keap1 and PTGS2 decreased significantly based on immunohistochemistry and western-blot. Conclusion: CQ could reduce neuronal ferroptosis and seizures via the P62-Keap1-Nrf2-GPX4-ferroptosis pathway, and we preliminary investigated the possible link between autophagy and ferroptosis.

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“…As GSH acts as a major antioxidant in the brain, this impaired GSH redox status can lead to further oxidative damage and redox dysregulation, which is associated with cognitive deficits, neuronal death, and mortality in animal epilepsy models. Indeed, loss of glutathione peroxidase 4, a oxidation-resistant selenoprotein that utilizes GSH, leads to lipid peroxidation and subsequent ferroptosis, which is also found in epilepsy models ( Ingold et al, 2018 ; Cai and Yang, 2021 ).…”

Section: Oxidative Stress In Epilepsymentioning

confidence: 99%

“…In the reduced state, HMGB1 acts as a chemoattractant. In the oxidized state with two nearby cysteines forming a disulfide bond and the third cysteine unmodified, HMGB1 acts as a proinflammatory cytokine (Yang et al, 2021) which can interact with TLR4 (Balosso et al, 2014). Overoxidation inhibits all HMGB1 functions.…”

Section: Oxidative Stress and Redox Regulation Of Neuroinflammationmentioning

confidence: 99%

Crosstalk between neuroinflammation and oxidative stress in epilepsy

Fabisiak

Patel²

2022

Front. Cell Dev. Biol.

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The roles of both neuroinflammation and oxidative stress in the pathophysiology of epilepsy have begun to receive considerable attention in recent years. However, these concepts are predominantly studied as separate entities despite the evidence that neuroinflammatory and redox-based signaling cascades have significant crosstalk. Oxidative post-translational modifications have been demonstrated to directly influence the function of key neuroinflammatory mediators. Neuroinflammation can further be controlled on the transcriptional level as the transcriptional regulators NF-KB and nrf2 are activated by reactive oxygen species. Further, neuroinflammation can induce the increased expression and activity of NADPH oxidase, leading to a highly oxidative environment. These factors additionally influence mitochondria function and the metabolic status of neurons and glia, which are already metabolically stressed in epilepsy. Given the implication of this relationship to disease pathology, this review explores the numerous mechanisms by which neuroinflammation and oxidative stress influence one another in the context of epilepsy. We further examine the efficacy of treatments targeting oxidative stress and redox regulation in animal and human epilepsies in the literature that warrant further investigation. Treatment approaches aimed at rectifying oxidative stress and aberrant redox signaling may enable control of neuroinflammation and improve patient outcomes.

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Ferroptosis and Its Role in Epilepsy

Cited by 53 publications

References 94 publications

Targeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders

Targeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders

Chloroquine exerts antiepileptic and neuroprotective effects through the P62-Keap1-Nrf2-GPX4-ferroptosis pathway in pentatetrazone-induced epileptic rat model

Crosstalk between neuroinflammation and oxidative stress in epilepsy

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