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 (ED50 = 161 mg/kg) or GBP (ED50 = 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.
Footnotes
-
This research was supported by government funding. Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.106.105999.
-
ABBREVIATIONS: AED, antiepileptic drug; NCS, nonconvulsive seizure(s); EEG, electroencephalography/electroencephalographic; GBP, gabapentin; EXM, ethosuximide; SWD, spike-and-wave discharge; LVACC, low-voltage-activated calcium channel; MCAo, middle cerebral artery occlusion; SWS, slow-wave sleep; DIV, days in vitro; H/H, hypoxia/hypoglycemia; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; ANOVA, analysis of variance.
- Received April 10, 2006.
- Accepted May 23, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|