title: Nefiracetam attenuates post-ischemic nonconvulsive seizures in rats and protects neuronal cell death induced by veratridine and glutamate.
abstract: OBJECTIVE
  Stroke 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.
  
  
  METHODS
  In the in vivo study, rats received 24h permanent middle cerebral artery occlusion. NEF was administered intravenously either at 15 min post-injury but prior to the first NCS event (30 mg/kg, pre-NCS treatment) or immediately after the first NCS occurred (30 or 60 mg/kg, post-NCS treatment). In the in vitro study, neuronal cell cultures were exposed to veratridine or glutamate and treated with NEF (1-500 nM).
  
  
  RESULTS
  The NEF pre-NCS treatment significantly reduced the NCS frequency and duration, whereas the higher NEF dose (60 mg/kg) was required to achieve similar effects when given after NCS occurred. The NEF treatment also dose-dependently (5-500 nM) protected against neuronal cell death induced by veratridine as measured by MTT cell viability assay, but higher doses (250-500 nM) were required against glutamate toxicity.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Branch of Brain Trauma and Neuroprotection and Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. may.lu@us.army.mil
authors.forename: Xi-Chun May
authors.initials: XC
authors.lastname: Lu
authors.forename: Jitendra R
authors.initials: JR
authors.lastname: Dave
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Cao
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Liao
authors.forename: Frank C
authors.initials: FC
authors.lastname: Tortella
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004569:Electroencephalography; D004829:Epilepsy, Generalized / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D007275:Injections, Intravenous; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014701:Veratridine / Q000633:toxicity*
chemical_list: D018696:Neuroprotective Agents; D011760:Pyrrolidinones; C058876:nefiracetam; D014701:Veratridine