ERK1/2 regulates Epileptic Seizures by modulating the DRP1 mediated Mitochondrial Dynamic

Abstract

Abstract Objective: After seizures, the hyperactivation of Extracellular signal-regulated kinases (ERK1/2) causes dysfunction of mitochondrial. Through the guideline of Dynamin-related protein 1（DRP1）, ERK1/2 plays a role in the pathogenesis of several illnesses, for instance cancer, Parkinson's, and Alzheimer's. However, it is unclear whether DRP1 function is regulated by ERK1/2 in the pathogenesis of seizures. Method: LiCl-Pilocarpine was injected intraperitoneally to establish a status epilepticus (SE) rat for this study. Before SE induction, PD98059 and Mdivi-1 were injected intraoperatively. The number of seizures and the latency of the first seizure were then monitored. The analysis of Western blot was also used to measure the phosphorylated and total ERK1/2 and DRP1 protein expression levels in the rat hippocampus. In addition, immunohistochemistry revealed the distribution of ERK1/2 and DRP1 in hippocampal neurons CA1 and CA3. Results: Both PD98059 and Mdivi-1 reduced rats' susceptibility to epileptic seizures, according to behavioral findings. By inhibiting ERK1/2 phosphorylation, the Western blot revealed that PD98059 indirectly reduced p-DRP1 expression level at the Ser616. Eventually, the ERK1/2 and DRP1 were distributed in the cytoplasm of neurons by immunohistochemistry. Conclusions: p-DRP1-Ser616 expression, which may regulate the pathogenesis of epilepsy by inhibiting DRP1-mediated excessive mitochondrial fission, is downregulated when ERK1/2 signaling pathways are inhibited.