The AMPAR Antagonist Perampanel Regulates Neuronal Necroptosis via Akt/GSK3β Signaling After Acute Traumatic Injury in Cortical Neurons

Abstract

Background: Perampanel is a highly selective and non-competitive α-amino-3-hydroxy- 5 -methyl-4-isoxazole propionate (AMPA) receptor (AMPAR) antagonist, which has been licensed as an orally administered antiepileptic drug in more than 55 countries. Recently, perampanel was found to exert neuroprotective effects in hemorrhagic and ischemic stroke models. Objective: In this study, the protective effect of perampanel was investigated. Methods: The protective effect of perampanel was investigated in an in vitro Traumatic Neuronal Injury (TNI) model in primary cultured cortical neurons. Results: We found that perampanel significantly preserved morphological changes, attenuated lactate dehydrogenase (LDH) release and inhibited caspase-3 activation after TNI. The TNI-induced necroptosis, as evidenced by flow cytometry, was markedly reduced by perampanel treatment. The results of western blot showed that perampanel decreased the expression and phosphorylation of the necroptotic factors, receptor protein interacting kinase 1 (RIPK1) and RIPK3. In addition, treatment with perampanel increased the phosphorylation of Akt and GSK3β in a time-dependent manner up to 24 h after TNI. Treatment with the Akt inhibitor LY294002 partially reversed the protective effects of perampanel. Conclusion: Our present data suggest that necroptosis plays a key role in the pathogenesis of neuronal death after TNI, and that perampanel might have therapeutic potential for patients with Traumatic Brain Injury (TBI).