Abstracts

Rationale: Limitation of antiepileptic drugs (AED) penetration by P-glycoprotein (Pgp) efflux transporter at the blood brain barrier is one of the most studied theories of therapeutic failure in epilepsy. Signaling events that have been postulated to drive Pgp expression in response to seizure activity include the activation of N-Methyl-D-aspartate receptors (NMDA-R), cyclooxygenase-2 enzyme (COX-2) and EP1- metabotropic receptor. In this study, we aimed to identify clinical factors associated with AED resistance. We also examined the hypothesis of association between AED resistance and the C3435T polymorphism on the MDR1 gene as well as other polymorphisms in genes that might be involved in P-glycoprotein regulation, including EP1 gene, PTGS2 gene, and GRIN1 gene; after adjustment for relevant clinical covariates. Methods: DNA was extracted from oral mucosa epithelial cells obtained from 107 pediatric (aged: 1-19 years-old) patients with epilepsy. Of those, 61 were classified as responders and 46 as non-responders based on their AED response. Medical records were reviewed for evaluation of clinical variables. Genotypic and allelic frequencies for the following polymorphisms: EP1 gene (rs10416814, rs3810254), PTGS2 gene (rs689466, rs689470), GRIN1 gene (rs28489906, rs2301363), and MDR1 gene (rs1045642) were determined by Real Time PCR. Results: Children with an abnormal EEG had 13.3 times higher odds (95%CI: 2.12-83.31) of being drug-resistant than children with normal EEG. Also, children with a cryptogenic (OR = 8.2, 95%CI: 1.42-47.24) and symptomatic (OR = 13.2, 95%CI: 2.11-82.91) epilepsy had significantly greater odds of being drug-resistant than children with idiopathic epilepsy. Children with multiple types of seizures showed higher odds (OR = 8.7, 95%CI: 1.71-44.52) of being drug-resistant than those with focal epilepsy. Significant differences in genotype frequency were observed between drug-resistant and drug-responsive patients for the rs1045642 MDR1 gene C/T (P=0.03) and rs10416814 EP1 gene A/T polymorphisms (P=0.04). For both polymorphisms, the heterozygous genotype was less frequent while the mutant homozygote genotype was more frequent among drug-resistant patients. No significant association between PTGS2 and GRIN1 polymorphisms and drug-resistance was found either in the crude or adjusted analyses. Conclusions: The present findings support a possible role of the MDR1 and EP1 genes in epilepsy pharmacoresistance. They also show that the association of polymorphisms with drug-resistance could be affected by clinical factors. Thus, this study highlights the multifactorial nature of drug-resistance in epilepsy. This work was supported by grants from the NIH (NCRR Award Number U54-RR 026139-01A1 & NIMHD Award Number 8U54-MD 007587-03) to the PRCTRC at the UPR-MSC and the RCMI-Clinical Research Center grant support (Grant Number G12RR03051, UPR-MSC).