EJMS

Abstract

Background/Aims: Many studies suggested that overexpression of the multidrug transporter P-glycoprotein in the hippocampal region leads to decreased levels of antiepileptic drugs and contributes to pharmacoresistance. Statins have an inhibitory effect on P-glycoprotein, in addition to their anti-inflammatory and neuroprotective effects. Herein, anti-seizure effects of statins in a rat model of drug-resistant seizures induced by pilocarpine and treated with phenytoin were investigated. Methods: Atorvastatin was administered to male Wistar rats 14 days prior to induction of status epilepticus by pilocarpine. Two hours after status epilepticus, and for two days, rats were treated with phenytoin. Phenytoin brain/plasma ratios were measured and brains were evaluated for neurodegeneration and P-glycoprotein expression. Results: Status epilepticus occurred in 60% of atorvastatin pretreated rats versus 88.9% of control rats. A significant increase was observed in pilocarpine dose required to induce a status epilepticus with less severity and no mortality in atorvastatin pretreated rats. Treatment with phenytoin partially suppressed status epilepticus in rats, with seizure severity score of 3.2 ± 1.39 and 37.7% mortality. However, a significant control of status epilepticus by phenytoin was obtained in atorvastatin pretreated rats with seizure severity score of 2.83 ± 0.75 and no mortality. In addition, atorvastatin reduced pilocarpine-induced hippocampal neuron death, decreased P-glycoprotein expression significantly, and increased phenytoin brain-to-plasma ratio significantly (2.64±0.43 versus 1.67±0.21). Conclusion: Atorvastatin significantly improves the anticonvulsive action of phenytoin. The results suggest that the administration of phenytoin in combination with atorvastatin may be a promising therapeutic strategy in pharmacoresistant epileptic patients.