Perampanel Mitigates Neuroinflammation and Nitrosative Stress in a Rat Model of Traumatic Brain Injury

Abstract Traumatic brain injury (TBI) is a common cause of disability and mortality across all age groups. Inflammation is a crucial contributor to secondary injury following brain trauma. With advancements in surgical techniques and procedures, we aimed to identify a rational, safe, and efficacious pharmacological intervention that can ameliorate post-TBI symptoms, minimise associated complications, and enhance patient prognosis and quality of life. Perampanel is an oral, potent, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist. By antagonising AMPA receptors, a reduction in nitrate production can be achieved, thereby influencing crucial signalling factors involved in the pathway that induces inflammation. In this study, we investigated the potential neuroprotective effects of perampanel on rat neurones following TBI, using a rat model of cortical impact. The oral administration of perampanel effectively mitigated TBI-induced cellular oedema, reduced neuronal cell death, and attenuated tissue nitric oxide (NO) production in rats. Oral administration of perampanel results in a reduction in neuronal nitric oxide synthase (nNOS) levels accompanied by a concurrent decrease in downstream cyclic guanosine monophosphate (cGMP). Furthermore, at 6, 12, and 24 h post-injury, a decline in inflammatory factors and an increase in anti-inflammatory factors were observed. The same trend was further strengthened by the addition of an nNOS inhibitor to perampanel. Therefore, we conclude that perampanel is effective in preserving neurological function following traumatic brain injury (TBI) in rats by attenuating nitrate production, reducing inflammation, mitigating neuronal cell death, and acting through the nNOS-cGMP pathway.