QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.107.126250v1 323/1/165    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kim, J. Articles by Gale, K. Search for Related Content PubMed PubMed Citation Articles by Kim, J. Articles by Gale, K.

NEUROPHARMACOLOGY

Antiepileptic Drug-Induced Neuronal Cell Death in the Immature Brain: Effects of Carbamazepine, Topiramate, and Levetiracetam as Monotherapy versus Polytherapy

Interdisciplinary Program in Neuroscience (J.K., A.K., K.G.), Departments of Pharmacology (J.K., A.K., K.G.), and Pediatrics (A.K.), Georgetown University Medical Center, Washington, DC

The aim of this study was to test the potential neurotoxicity of three antiepileptic drugs (AEDs), carbamazepine (5H-dibenzepine-5-carboxamide), topiramate [2,3:4,5-bis-O-(1-methylethylidene)--D-fructopyranose sulfamate], and levetiracetam [2-(2-oxopyrrolidin-1-yl)butanamide], in the developing rat brain, when given alone or in combinations. The extent of cell death induced by AEDs was measured in several brain regions of rat pups (postnatal day 8) by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay 24 h after drug treatment. Carbamazepine alone did not increase neurodegeneration when given in doses up to 50 mg/kg, but it induced significant cell death at 100 mg/kg. When combined with phenytoin, carbamazepine, 50 but not 25 mg/kg, significantly exacerbated phenytoin-induced cell death. Although topiramate (20–80 mg/kg) alone caused no neurodegeneration, all doses exacerbated phenytoin-induced neurodegeneration. Levetiracetam (250–1000 mg/kg) alone did not induce cell death, nor did it exacerbate phenytoin-induced neurodegeneration. Of the combinations examined, only that of levetiracetam (250 mg/kg) with carbamazepine (50 mg/kg) did not induce neurodegeneration. Our data underscore the importance of evaluating the safety of combinations of AEDs given during development and not merely extrapolating from the effects of exposure to single drugs. Although carbamazepine and topiramate alone did not induce neuronal death, both drugs exacerbated phenytoin-induced cell death. In contrast, because cotreatment with levetiracetam and carbamazepine did not enhance cell death in the developing brain, it may be possible to avoid proapoptotic effects, even in polytherapy, by choosing appropriate drugs. The latter drugs, as monotherapy or in combination, may be promising candidates for the treatment of women during pregnancy and for preterm and neonatal infants.

Address correspondence to: Dr. Karen Gale, Georgetown University, W215 Research Building, 3970 Reservoir Road, N.W., Washington, DC 20057. E-mail: galek{at}georgetown.edu