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 ϭ 161 mg/kg) or GBP (ED 50 ϭ 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 ϭ 0.475; P Ͻ 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 antiseizure 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.

Ethosuximide Induces Hippocampal Neurogenesis and Reverses Cognitive Deficits in an Amyloid-β Toxin-induced Alzheimer Rat Model via the Phosphatidylinositol 3-Kinase (PI3K)/Akt/Wnt/β-Catenin Pathway

“…It is of potential therapeutic value in other neuropsychiatric disorders (25,52). In the present study, we demonstrated that ETH promotes adult hippocampal neurogenesis both in vitro and in vivo.…”

“…This dose was selected on the basis of therapeutically or pharmacologically relevant levels of ETH, as described earlier (25,30). Rats in the control group received normal saline as vehicle.…”

“…NSC cultures were incubated with different concentrations of ETH (25,50,100,150,200, and 400 M) for 48 h. ETH significantly enhanced NSC proliferation at 50, 100, and 150 M in the alamar blue assay (Fig. 1A).…”

“…NSCs were plated in black bottom 96-well microplates at a density of 10,000 cells/well. The cells were treated with different concentrations of ETH (25,50,100,200, and 400 M) dissolved in DMSO for 48 h. Vehicle-treated cells served as a control. After treatment, alamar blue was added, and cells were incubated at 37°C for 2 h. Background florescence was measured by adding 10 l of alamar blue solution/well in medium having no cells.…”

“…ETH reduces agedependent toxicity in C. elegans motor neurons against mutant TAR DNA-binding protein-43, involved in pathogenesis of amyotrophic lateral sclerosis (24). It has been found to reduce infarct volume in an ischemic brain injury rat model (25) and to protect neurons in the hippocampal slice cultures against oxygen and glucose deprivation (25). Also, it promotes neuronal differentiation of rat muscle-derived stem cells in vitro (26) and differentiation of neonatal rat forebrain stem cells to microtubule-associated protein-2-positive neural cells (27).…”