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

Abstract

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.

D-Penicillamine Reveals the Amelioration of Seizure-Induced Neuronal Injury via Inhibiting Aqp11-Dependent Ferroptosis

“…It was intriguing that treatment with DPA significantly alleviated the seizure behavior including generalized tonic-clonic seizures ( Supplementary Movie ). In addition, other indices for seizure evaluation, which include seizure score, number of seizures within 90 min and seizure duration [ 12 ], were also analyzed in our present work. It was found that DPA remarkably decreased the seizure score ( Figure S1A ), seizure frequency (number of seizures within 90 min in Figure S1B ) and seizure duration ( Figure S1C ).…”

“…All animal experiments were conducted in strict accordance with principles presented in the National Institute of Health for the Care and Use of Laboratory Animals and approved by the Institutional Animal Ethics Committee of Central South University (approved number: 2020–0019). To prepare the seizure mouse model, the mice underwent the intrahippocampal injection of KA as described in our previous investigation [ 12 , 25 ]. For short, mice were anesthetized with sodium phenobarbital (50 mg/kg, i.p.)…”

“…The LPO level of hippocampus tissues was determined by a Lipid Peroxidation kit (A106, Jiancheng Biotechnology, China). Cellular lipid ROS level was analyzed with a C11-BODIPY (581/591)-labelled method according to our previous investigation [ 12 ]. In brief, HT22 cells after drug treatments were trypsinized and incubated with C11-BODIPY (581/591) (2 μmol/L) for 15 min at 37 °C.…”

“…Ferroptotic cells usually have the characteristics of iron-dependency and overproduction of lethal lipid peroxides. Our previous investigations delineate that ferroptosis are activated in multiple seizure rodent models induced by various chemical reagents such as kainic acid (KA), pentylenetetrazole, pilocarpine and ferric chloride [ 10 , 11 , 12 , 13 ]. Furthermore, the seizure activity and associated neuronal injury are remarkably prevented when treatment with ferroptosis inhibitors including ferrostatin-1 (Fer-1) or liproxstatin-1 (Lip-1), suggesting a promising approach in curing seizure disorders and protecting from brain injury via targeting ferroptosis.…”

Ferroptosis and Its Role in Epilepsy

“…As a traditional anticancer drug, lapatinib can modulate oxidative stress and inhibit tumor progression. Recently, lapatinib was found to prevent kainic acid-induced seizures and ferroptosis in mice by restoring GPX4 (Jia et al, 2020). Interestingly, ferroptosis pathway-related molecules are also affected by AEDs and other compounds.…”