ERK1/2 Regulates Epileptic Seizures by Modulating the DRP1‐Mediated Mitochondrial Dynamic

Abstract

After seizures, the hyperactivation of extracellular signal‐regulated kinases (ERK1/2) causes mitochondrial dysfunction. Through the guidance of dynamin‐related protein 1 (DRP1), ERK1/2 plays a role in the pathogenesis of several illnesses. Herein, we speculate that ERK1/2 affects mitochondrial division and participates in the pathogenesis of epilepsy by regulating the activity of DRP1. LiCl‐Pilocarpine was injected intraperitoneally to establish a rat model of status epilepticus (SE) for this study. Before SE induction, PD98059 and Mdivi‐1 were injected intraperitoneally. The number of seizures and the latency period before the onset 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 neurons of hippocampal CA1 and CA3. Both PD98059 and Mdivi‐1 reduced the susceptibility of rats to epileptic seizures, according to behavioral findings. By inhibiting ERK1/2 phosphorylation, the Western blot revealed that PD98059 indirectly reduced the phosphorylation of DRP1 at Ser616 (p‐DRP1‐Ser616). Eventually, the ERK1/2 and DRP1 were distributed in the cytoplasm of neurons by immunohistochemistry. Inhibition of ERK1/2 signaling pathways downregulates p‐DRP1‐Ser616 expression, which could inhibit DRP1‐mediated excessive mitochondrial fission and then regulate the pathogenesis of epilepsy.