Non-Competitive AMPA Receptor Antagonist Perampanel Inhibits Ischemia-Induced Neurodegeneration and Behavioral Deficits in Focal Cortical Pial Vessel Disruption Stroke Model

Glutamate receptors represent a potential target for neuroprotection in neurodegener-ative neurological conditions. Perampanel, a non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) antagonist, is clinically approved for the management of epilepsy. Perampanel’s neuroprotective ef-fects have been reported in global and focal cerebral ischemia models, but the cellular mechanisms remain incompletely understood. Here we investigated the potential neuroprotective effects of perampanel in rats subjected to pial vessel disruption (PVD), which mimics a focal cortical non-reperfusion ischemic stroke model. Perampanel was given intraperitoneally (3mg/kg body weight) 1 hr after PVD surgery and once daily for two days post-surgery. On the fourth day post PVD, animal behavioral assays and imaging, biochemical and electrophysiological analyses were performed. Compared to vehicle control, perampanel in PVD-treated rats significantly inhibited hippocampal neurodegeneration and long-term potentiation deficits. Perampanel also attenuated PVD-induced motor deficits, depressive/anxiety-like behaviors, and hippocam-pal-dependent cognitive impairment. In addition, perampanel prevented the PVD-induced downregulation of surface-expressed GluA1 and GluA2 AMPARs and increased phosphorylation of GluA1 at S831 and S845. Molecular docking analysis revealed perampanel binding to transmembrane regions M1, M3 and M4 of GluA1 and GluA2 subunits. Together, our results show that perampanel attenuated PVD-induced neurodegeneration and behavioral deficits by blocking AMPARs and decreasing GluA1 and GluA2 internalization. In addition, this study shows the neuroprotective potential of perampanel through the inhibition of neuroinflammation mediated by ac-tivated microglia and astrocytes following cerebral ischemia.