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NEUROPHARMACOLOGY

Antiepileptic Drug Treatment of Nonconvulsive Seizures Induced by Experimental Focal Brain Ischemia

Walter Reed Army Institute of Research, Silver Spring, Maryland (A.J.W., F.C.T., X.M.L., J.A.H.); and Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (J.E.M.)

Nonconvulsive seizures (NCSs) after traumatic and ischemic brain injury are often refractory to antiepileptic drug therapy and are associated with a decline in patient outcome. We recently characterized an in vivo rat model of focal brain ischemia-induced NCS and here sought to evaluate potential pharmacological treatments. Electroencephalographic activity was recorded continuously for 24 h in freely behaving rats subjected to permanent middle cerebral artery occlusion (MCAo). Rats were treated with an antiepileptic drug from one of seven different drug classes at ED₅₀ and 2x ED₅₀ doses (as reported in other rat seizure models), delivered as a single i.v. injection 20 min post-MCAo. Vehicle-treated rats (n = 9) had an 89% incidence of NCS with an average number of NCS of 8.6 ± 1.9. The latency to onset of NCS was 32.5 ± 3.4 min post-MCAo with an average duration of 49.1 ± 8.2 s/event. The high doses of ethosuximide, gabapentin, fos-phenytoin, and valproate significantly reduced the incidence of NCS (11, 14, 14, and 38%, respectively), whereas midazolam, phenobarbital, and dextromethorphan had no significant effect at either dose. Across treatment groups, there was a low but significant correlation between the number of NCS events per animal and volume of brain infarction (r = 0.352). Antiepileptic drug therapy that prevented the occurrence of NCS also reduced mortality from 26 to 7%. Based on combined effects on NCS, infarction, neurological recovery, and mortality, ethosuximide and gabapentin were identified as having the best therapeutic profile.

Address correspondence to: Dr. Anthony J. Williams, Department of Applied Neurobiology, Division of Neurosciences, Walter Reed Army Institute of Research, Silver Spring, MD 20910. E-mail: anthony.williams{at}na.amedd.army.mil

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