Evaluation of Gabapentin and Ethosuximide for Treatment of Acute Nonconvulsive Seizures following Ischemic Brain Injury in Rats

Abstract

Acute seizures following brain injury have been associated with a worsening of patient outcome, but they are often undiagnosed and untreated when they occur without motor convulsions. Here, we sought to compare the antiseizure profile of ethosuximide (EXM; 125-312.5 mg/kg i.v.) and gabapentin (GBP; 0.3-50 mg/kg. i.v.) in a rat model of nonconvulsive seizures (NCS) induced by brain ischemia. Seizures were detected by continuous electroencephalographic monitoring for 24 h following permanent middle cerebral artery occlusion (MCAo). Both "preseizure" and "postseizure" treatment effects were evaluated. Control rats experienced a 91% incidence of NCS (averaging 10-11 NCS/rat), which was significantly reduced following preseizure treatment (delivered 20 min post-MCAo) with either EXM (ED(50) = 161 mg/kg) or GBP (ED(50) = 10.5 mg/kg). In contrast to preseizure treatment effects, only GBP reduced NCS when given after the first seizure event. A further, albeit nonsignificant, 20% reduction in NCS incidence was measured when given in combination postseizure. Drug treatment also reduced infarct volume, which was positively correlated to the number of NCS events (r = 0.475; P < 0.001). EXM and GBP treatment of cultured neurons exposed to neurotoxic or ischemic insults showed no neuroprotective effects, suggesting that in vivo neuroprotection can be attributed to anti-seizure effects. We conclude that EXM and GBP significantly attenuate NCS in a dose-related manner and may help to improve patient outcome from brain ischemia-induced seizure activity.