Abstracts

Accumulating data indicate that seizure-induced upregulation of the multidrug transporter, P-glycoprotein (Pgp), can contribute to pharmacoresistance. Enhanced Pgp expression in brain capillary endothelial cells seems to limit brain penetration of antiepileptic drugs. Thus, interaction with factors mediating seizure-induced upregulation of Pgp may be one strategy to limit the development of pharmacoresistance. There is evidence that cyclooxygenase (COX) may be involved in seizure-induced upregulation of Pgp. On one hand COX is induced by seizure activity and on the other hand COX can induce Pgp expression. In the present study, we tested whether COX inhibition can prevent induction of Pgp by seizure activity., Status epilepticus (SE) was induced in rats by fractionated pilocarpine administration (10 mg/kg i.p. every 30 min). Eighteen animals received daily i.p. injections of the COX inhibitor indomethacin (2.5 mg/kg i.p. 2 times daily) starting at the day before status epilepticus induction. Twelve rats received corresponding vehicle injections. SE duration was limited to 90 min using diazepam. Rats were perfused two days following SE. Pgp expression was analyzed in the hippocampus and adjacent cortex by immunhistochemistry. Expression of both groups with SE was compared with that of an additional control group (n=8) which received vehicle injections, but in which no SE was induced., Severity of SE was not influenced by indomethacin treatment. However, exitus during SE and at the day following SE was more frequent in the group of indomethacin treated rats (44%) as compared to vehicle treated rats (8%). Pgp expression was significantly upregulated in the hippocampus and adjacent cortex following SE. Indomethacin treatment prevented this upregulation both in the hippocampus and the cortex. A pronounced indomethacin-mediated neuroprotection was obvious in the piriform cortex by visual inspection of the brain sections. Currently, we are studying the degree of neurodegeneration in the hippocampus by neuronal cell counts to evaluate whether neuroprotection was also achieved in this brain region., The data indicate that cyclooxygenase plays a critical role in seizure-induced upregulation of Pgp. Inhibition of inflammatory cascades may be a valid strategy to prevent Pgp-mediated pharmacoresistance. Further validation of this strategy is necessary with a focus on safety., (Supported by National Institute of Environmental Health Sciences, Division of Intramural Research.)