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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 25, 2006; DOI: 10.1124/jpet.106.105999

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*Compound via MeSH
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*ETHOSUXIMIDE
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*Seizures


Received for publication April 14, 2006.
Revised May 23, 2006.
Accepted for publication May 23, 2006.

Evaluation of Gabapentin and Ethosuximide for Treatment of Acute Non-Convulsive Seizures (NCS) Following Ischemic Brain Injury in Rats

Anthony J. Williams 1*, Charisma C. Bautista 1, Ren-Wu Chen 1, Jitendra R. Dave 1, Xi-Chun M. Lu 1, Frank C. Tortella 1, Jed A. Hartings 1

1 Walter Reed Army Institute of Research

* Address correspondence to: E-mail: anthony.williams{at}na.amedd.army.mil

Abstract

Acute seizures following brain injury have been associated with a worsening of patient outcome, but are often undiagnosed and untreated when they occur without motor convulsions. Here we sought to compare the anti-seizure 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 non-convulsive seizure (NCS) induced by brain ischemia. Seizures were detected by continuous electroencephalographic (EEG) monitoring for 24h following permanent middle cerebral artery occlusion (MCAo). Both 'pre-seizure' and 'post-seizure' treatment effects were evaluated. Control rats experienced a 91% incidence of NCS (averaging 10-11 NCS/rat), which was significantly reduced following pre-seizure treatment (delivered 20 min. post-MCAo) with either EXM (ED50=161 mg/kg) or GBP (ED50=10.5 mg/kg). In contrast to pre-seizure treatment effects, only GBP reduced NCS when given after the first seizure event. A further, albeit non-significant, 20% reduction in NCS incidence was measured when given in combination post-seizure. 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.


Key words: brain injury, ethosuximide, gabapentin, neuroprotection, seizure, stroke


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