Nefiracetam attenuates post-ischemic nonconvulsive seizures in rats and protects neuronal cell death induced by veratridine and glutamate

Abstract

AimsStroke patients are at a high risk of developing post-ischemic seizures and cognitive impairment. Nefiracetam (NEF), a pyrrolidone derivative, has been shown to possess both anti-epileptic and cognitive-enhancing properties. In this study the anti-seizure effects of NEF were evaluated in a rat model of post-ischemic nonconvulsive seizures (NCSs). Its potential mechanisms were investigated in neuronal cell culture assays of neurotoxicity associated with ischemic brain injury and epileptogenesis. Main methodsIn the in vivo study, rats received 24h permanent middle cerebral artery occlusion. NEF was administered intravenously either at 15min post-injury but prior to the first NCS event (30mg/kg, pre-NCS treatment) or immediately after the first NCS occurred (30 or 60mg/kg, post-NCS treatment). In the in vitro study, neuronal cell cultures were exposed to veratridine or glutamate and treated with NEF (1–500nM). Key findingsThe NEF pre-NCS treatment significantly reduced the NCS frequency and duration, whereas the higher NEF dose (60mg/kg) was required to achieve similar effects when given after NCS occurred. The NEF treatment also dose-dependently (5–500nM) protected against neuronal cell death induced by veratridine as measured by MTT cell viability assay, but higher doses (250–500nM) were required against glutamate toxicity. SignificanceThe anti-seizure property of NEF was demonstrated in a clinically relevant rat model of post-ischemic NCS. The preferential effects of NEF against in vitro veratridine toxicity suggest the involvement of its modulation of sodium channel malfunction. Future studies are warranted to study the mechanisms of NEF against ischemic brain injury and post-ischemic seizures.