Perampanel, an AMPAR antagonist, alleviates experimental intracerebral hemorrhage-induced brain injury via necroptosis and neuroinflammation

Spontaneous intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and morbidity due to the lack of effective therapies. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist perampanel has been reported to alleviate early brain injury following subarachnoid hemorrhage and traumatic brain injury by reducing reactive oxygen species, apoptosis, autophagy, and necroptosis. Necroptosis is a caspase-independent programmed cell death mechanism that serves a vital role in neuronal cell death following ICH. However, the precise role of necroptosis in perampanel-mediated neuroprotection following ICH has not been confirmed. The present study aimed to investigate the neuroprotective effects and potential molecular mechanisms of perampanel in ICH-induced early brain injury by regulating neural necroptosis in C57BL/6 mice and in a hemin-induced neuron damage cell culture model. Mortality, neurological score, brain water content, and neuronal death were evaluated. The results demonstrated that perampanel treatment increased the survival rate and neurological score, and increased neuron survival. In addition, perampanel treatment downregulated the protein expression levels of receptor interacting serine/threonine kinase (RIP) 1, RIP3, and mixed lineage kinase domain like pseudokinase, and of the cytokines IL-1β, IL-6, TNF-α, and NF-κB. These results indicated that perampanel-mediated inhibition of necroptosis and neuroinflammation ameliorated neuronal death in vitro and in vivo following ICH. The neuroprotective capacity of perampanel was partly dependent on the PTEN pathway. Taken together, the results of the present study demonstrated that perampanel improved neurological outcomes in mice and reduced neuronal death by protecting against neural necroptosis and neuroinflammation.