Perampanel improves cognitive function in epilepsy by targeting AMPA receptor subunit GluR2-mediated endoplasmic reticulum stress and synaptic plasticity.

AIMS: This study aimed to explore the action mechanism of Perampanel (PER) in epilepsy treatment, particularly the associations with endoplasmic reticulum stress (ERS). METHODS: Epilepsy mice model was induced by injecting kainic acid (KA) into hippocampus of mice, and KA-stimulated hippocampal neurons were used as in vitro cell model. Cognitive function of mice was evaluated by Novel Object Recognition and Morris Water maze tests. Hematoxylin-eosin and Nissl staining were conducted to observe neuron damage. Synaptic plasticity was evaluated by Golgi staining, immunofluorescence staining of microtubule-associated protein (MAP2) and synaptic function proteins expression. The 4-phenylbutyric acid (4-PBA) was used to inhibit ERS in cells. RESULTS: PER treatment markedly ameliorated epileptic seizure behaviors, improved the spatial learning and memory functions, and hippocampal neuron injury of KA-induced epilepsy mice model. Moreover, KA-induced epilepsy mice showed reduced GluR2 expression, decreased dendritic spine density and expression of synaptic function proteins (SYP and PSD95) as well as elevated ERS-related proteins (GRP78, ATF4, CHOP, IRE1α and ATF6), while PER treatment could reverse such changes. Meanwhile, PER treatment could alleviate KA-induced neurotoxicity and synaptic plasticity deficits in hippocampal neurons. In terms of mechanism, GluR2 silencing reversed the protective effects of PER in KA-stimulated hippocampal neurons, and further inhibiting ERS using 4-PBA could offset the effects of GluR2 silencing. CONCLUSION: GluR2-mediated ERS may involve the improved effects of Perampanel in cognitive function of epilepsy patients by promoting synaptic plasticity.