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.

Keywords: ABC transporters; antiepileptic drugs; epilepsy; oxidative stress; pharmacoresistance.

Figure 1

Modulation of ABC efflux transporter at blood brain barrier (BBB) by oxidative stress: possible mechanism of pharmacoresistance in epilepsy. Epilepsy results when the balance between neuronal excitability and inhibition is tipped towards excitability (1); This imbalance increases production of brain ROS molecules, leading to oxidative stress (2); The elevated stress in turn aggravates the epileptic condition forming a vicious cycle (3); First line AEDs given as a treatment to patients with epilepsy also raises oxidative stress levels, which become undesirable for the patients (4); This oxidative stress through activation of various signaling molecules such as Nrf2, NF-KB, PPARα etc. (5) alters the basal transporter expression (6); The resulting consequence is increased efflux of AEDs from brain (7); which are substrate of these transporters resulting in pharmacoresistant phenotype (8). To address the problem of oxidative stress damage, antioxidants as an adjunct therapy along with AEDs and ketogenic diet seem promising as efficient neuroprotectants. However, their role in pharmacoresistance is still unclear.