Effect of Oxidative Stress on ABC Transporters: Contribution to Epilepsy Pharmacoresistance

Abstract

Epilepsy is a neurological disorder affecting around 1%–2% of population worldwide and its treatment includes use of antiepileptic drugs to control seizures. Failure to respond to antiepileptic drug therapy is a major clinical problem and over expression of ATP-binding cassette transporters is considered one of the major reasons for pharmacoresistance. In this review, we have summarized the regulation of ABC transporters in response to oxidative stress due to disease and antiepileptic drugs. Further, ketogenic diet and antioxidants were examined for their role in pharmacoresistance. The understanding of signalling pathways and mechanism involved may help in identifying potential therapeutic targets and improving drug response.

1,2,4-Triazole-based anticonvulsant agents with additional ROS scavenging activity are effective in a model of pharmacoresistant epilepsy

“…Clinically important consequence of the elevated ROS production is the overexpression of several proteins that belong to the group of ATP-binding cassette (ABC) transporters, that contribute to AEDs pharmacoresistance. 7 Therefore, it is desirable that new antiepileptic drug candidates combine antiseizure activity with the ability to reduce ROS generation in CNS cells. Unfortunately, many AEDs available on the market do not prevent the oxidative stress.…”

“…As it has been observed by some authors, although many conventional AEDs (e.g. phenobarbital, phenytoin, valproate, topiramate) reduce seizure frequency, they simultaneously induce free radicals generation 4,7 . Therefore, as concluded by other authors, the use of ROS scavengers may constitute a new approach to the treatment of epilepsy.…”

“…The abnormal concentration of the reactive oxygen/nitrogen species produced in human cells seems to be associated with the overexpression of ATP-binding cassette (ABC) transporters 7 . It results mainly from the effect of ROS/RNS on signal transduction pathways through a numerous transcription factors, e.g.…”

“…Since the main role of the ABC transporters is protecting cells from endogenous and exogenous toxins, these proteins interfere with drugs efficacy. Several studies showed that the overexpression of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins (MRPs) resulted in antiepileptic drugs (AEDs) resistance 7 . It is estimated that nearly 30% of epileptic patients suffer from the pharmacoresistant form of the disease 9 .…”

Epilepsy Disease and Nose-to-Brain Delivery of Polymeric Nanoparticles: An Overview

“…Alterations in ABC efflux transporter expression and activity occur in several neurological diseases. In fact, pharmaco-resistance to AEDs for epilepsy treatment is also associated with the overexpression of these transporters by extruding AEDs from their target site [38]. An interesting approach proposed to decrease the activity of ABC efflux transporters in neurological diseases including epilepsy is the use of direct inhibitors in order to promote a transient inhibition of ABC efflux transporters to prevent pharmaco-resistance due to overexpression of such transporters [39].…”