Lapatinib protects against epileptic seizures via halting glutathione
peroxidase 4-dependent ferroptosis
Abstract
Background and Purpose: Repetitive epileptic seizures trigger massive
neuronal death. Therefore, neuroprotection plays a role in preventing
neuronal death and inversely suppresses seizure generation.
Additionally, some studies have shown ferroptosis, featured by lipid
peroxidation (a dominant form of oxidative stress in the brain), is of
paramount importance in epileptic seizures. Lapatinib can play a
first-line anti-tumor role by targeting oxidative stress and a recent
work illustrates the improvement of encephalomyelitis in rodent models
after lapatinib treatment. We hypothesize whether lapatinib can protect
against ferroptosis in epileptic seizures via regulating lipid
peroxidation. Experimental Approach: The epileptic behavior of the mice
was recorded after intracranial injection of KA. Western blot and
RT-qPCR were used to detect the protein expression of 4-hydroxynonenal
(4-HNE) and glutathione peroxidase 4 (GPX4) and the mRNA expression of
prostaglandin endoperoxide synthase 2 (PTGS2) in vivo and in vitro. The
level of lipid reactive oxygen species (lipid ROS) in cells pretreated
with lapatinib was analyzed by flow cytometry. Key Results: Lapatinib
remarkably prevented KA-induced epileptic seizures in mice and
ferroptosis was involved in the neuroprotection of lapatinib. Compared
with the model group, western blot showed that lapatinib significantly
upregulated the levels of GPX4. In the ferroptotic cell death model,
lapatinib exerted neuroprotection via up-regulating GPX4. Treatment with
Ras-selective lethal small molecule 3 (RSL3), a selective GPX4 inhibitor
abrogated its anti-ferroptotic potential. Conclusions and Implications:
These results illustrated that lapatinib has neuroprotective potential
against KA-triggered epileptic seizures via suppressing GPX4-dependent
ferroptosis.