A Novel Approach to Refractory Epilepsy by Targeting Pgp Peripherally and Centrally: Therapeutic Targets and Future Perspectives

Abstract

Refractory epilepsy is a type of epilepsy involving seizures uncontrolled by first or second- line anticonvulsant drugs at a regular therapeutic dose. Despite considerable growth in epileptic pharmacotherapy, one-third of the patients are resistant to current therapies. In this, the mechanisms responsible for resistant epilepsy are either increased expulsion of antiepileptic drugs (AEDs) by multidrug resistance (MDR) transporters from the epileptogenic tissue or reduced sensitivity of drug in epileptogenic brain tissue. The difficulty to treat refractory epilepsy is because of drug resistance due to cellular drug efflux, use of drug monotherapy, and subtherapeutic dose administration. Increased expression of Pgp is also responsible for resistance epilepsy or refractory epilepsy. Increased glutamate expression via inhibition of cyclooxygenase-II (COX-II) enzyme also upregulate P-glycoprotein (Pgp) expression and augment instance of recurrent seizures. Peripheral and central inhibition of Pgp is a powerful tool to control this drug resistant epilepsy. Drug resistance primarily involves multidrug resistance (MDR1) gene responsible for encoding P-glycoprotein (Pg- P1 or MDR1). Currently, there is no drug under clinical practice which inhibits MDR1. The present review cites some drugs like Calcium Channel Blockers (CCBs), COX-II inhibitors, and glutamate receptors antagonists that inhibit P-gp. The exploitation of these targets may emerge as a beneficial approach for patients with drug-resistant epilepsy. The present review further highlights the mechanistic role of Pgp in drug-resistant epilepsy, glutamate role in drug efflux, and management approach.