Cargando…

Neuroprotective Effects of the Anti-cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis

Epilepsy is a complex neurological disorder characterized by recurrent and unprovoked seizures. Neuronal death process is implicated in the development of repetitive epileptic seizures. Therefore, cell death can be harnessed for ceasing seizures and epileptogenesis. Oxidative stress is regarded as a...

Descripción completa

Detalles Bibliográficos
Autores principales: Jia, Ji-Ning, Yin, Xi-Xi, Li, Qin, Guan, Qi-Wen, Yang, Nan, Chen, Kang-Ni, Zhou, Hong-Hao, Mao, Xiao-Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758233/
https://www.ncbi.nlm.nih.gov/pubmed/33362556
http://dx.doi.org/10.3389/fphar.2020.601572
_version_ 1783626895982592000
author Jia, Ji-Ning
Yin, Xi-Xi
Li, Qin
Guan, Qi-Wen
Yang, Nan
Chen, Kang-Ni
Zhou, Hong-Hao
Mao, Xiao-Yuan
author_facet Jia, Ji-Ning
Yin, Xi-Xi
Li, Qin
Guan, Qi-Wen
Yang, Nan
Chen, Kang-Ni
Zhou, Hong-Hao
Mao, Xiao-Yuan
author_sort Jia, Ji-Ning
collection PubMed
description Epilepsy is a complex neurological disorder characterized by recurrent and unprovoked seizures. Neuronal death process is implicated in the development of repetitive epileptic seizures. Therefore, cell death can be harnessed for ceasing seizures and epileptogenesis. Oxidative stress is regarded as a contributing factor of neuronal death activation and there is compelling evidence supporting antioxidants hold promise in abrogating seizure-related cell modality. Lapatinib, a well-known anti-cancer drug, has been traditionally reported to exert anti-tumor effect via modulating oxidative stress and a recent work illustrates the improvement of encephalomyelitis in rodent models after lapatinib treatment. However, whether lapatinib is beneficial for inhibiting neuronal death and epileptic seizure remains unknown. Here, we found that lapatinib remarkably prevented kainic acid (KA)-epileptic seizures in mice and ferroptosis, a newly defined cell death which is associated with oxidative stress, was involved in the neuroprotection of lapatinib. In the ferroptotic cell death model, lapatinib exerted neuroprotection via restoring glutathione peroxidase 4 (GPX4). Treatment with GPX4 inhibitor ras-selective lethal small molecule 3 (RSL3) abrogated its anti-ferroptotic potential. In a mouse model of KA-triggered seizure, it was also validated that lapatinib blocked GPX4-dependent ferroptosis. It is concluded that lapatinib has neuroprotective potential against epileptic seizures via suppressing GPX4-mediated ferroptosis.
format Online
Article
Text
id pubmed-7758233
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-77582332020-12-25 Neuroprotective Effects of the Anti-cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis Jia, Ji-Ning Yin, Xi-Xi Li, Qin Guan, Qi-Wen Yang, Nan Chen, Kang-Ni Zhou, Hong-Hao Mao, Xiao-Yuan Front Pharmacol Pharmacology Epilepsy is a complex neurological disorder characterized by recurrent and unprovoked seizures. Neuronal death process is implicated in the development of repetitive epileptic seizures. Therefore, cell death can be harnessed for ceasing seizures and epileptogenesis. Oxidative stress is regarded as a contributing factor of neuronal death activation and there is compelling evidence supporting antioxidants hold promise in abrogating seizure-related cell modality. Lapatinib, a well-known anti-cancer drug, has been traditionally reported to exert anti-tumor effect via modulating oxidative stress and a recent work illustrates the improvement of encephalomyelitis in rodent models after lapatinib treatment. However, whether lapatinib is beneficial for inhibiting neuronal death and epileptic seizure remains unknown. Here, we found that lapatinib remarkably prevented kainic acid (KA)-epileptic seizures in mice and ferroptosis, a newly defined cell death which is associated with oxidative stress, was involved in the neuroprotection of lapatinib. In the ferroptotic cell death model, lapatinib exerted neuroprotection via restoring glutathione peroxidase 4 (GPX4). Treatment with GPX4 inhibitor ras-selective lethal small molecule 3 (RSL3) abrogated its anti-ferroptotic potential. In a mouse model of KA-triggered seizure, it was also validated that lapatinib blocked GPX4-dependent ferroptosis. It is concluded that lapatinib has neuroprotective potential against epileptic seizures via suppressing GPX4-mediated ferroptosis. Frontiers Media S.A. 2020-12-10 /pmc/articles/PMC7758233/ /pubmed/33362556 http://dx.doi.org/10.3389/fphar.2020.601572 Text en Copyright © 2020 Jia, Yin, Li, Guan, Yang, Chen, Zhou and Mao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Jia, Ji-Ning
Yin, Xi-Xi
Li, Qin
Guan, Qi-Wen
Yang, Nan
Chen, Kang-Ni
Zhou, Hong-Hao
Mao, Xiao-Yuan
Neuroprotective Effects of the Anti-cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis
title Neuroprotective Effects of the Anti-cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis
title_full Neuroprotective Effects of the Anti-cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis
title_fullStr Neuroprotective Effects of the Anti-cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis
title_full_unstemmed Neuroprotective Effects of the Anti-cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis
title_short Neuroprotective Effects of the Anti-cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis
title_sort neuroprotective effects of the anti-cancer drug lapatinib against epileptic seizures via suppressing glutathione peroxidase 4-dependent ferroptosis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758233/
https://www.ncbi.nlm.nih.gov/pubmed/33362556
http://dx.doi.org/10.3389/fphar.2020.601572
work_keys_str_mv AT jiajining neuroprotectiveeffectsoftheanticancerdruglapatinibagainstepilepticseizuresviasuppressingglutathioneperoxidase4dependentferroptosis
AT yinxixi neuroprotectiveeffectsoftheanticancerdruglapatinibagainstepilepticseizuresviasuppressingglutathioneperoxidase4dependentferroptosis
AT liqin neuroprotectiveeffectsoftheanticancerdruglapatinibagainstepilepticseizuresviasuppressingglutathioneperoxidase4dependentferroptosis
AT guanqiwen neuroprotectiveeffectsoftheanticancerdruglapatinibagainstepilepticseizuresviasuppressingglutathioneperoxidase4dependentferroptosis
AT yangnan neuroprotectiveeffectsoftheanticancerdruglapatinibagainstepilepticseizuresviasuppressingglutathioneperoxidase4dependentferroptosis
AT chenkangni neuroprotectiveeffectsoftheanticancerdruglapatinibagainstepilepticseizuresviasuppressingglutathioneperoxidase4dependentferroptosis
AT zhouhonghao neuroprotectiveeffectsoftheanticancerdruglapatinibagainstepilepticseizuresviasuppressingglutathioneperoxidase4dependentferroptosis
AT maoxiaoyuan neuroprotectiveeffectsoftheanticancerdruglapatinibagainstepilepticseizuresviasuppressingglutathioneperoxidase4dependentferroptosis