Emerging therapeutic targets for epilepsy: preclinical insights

ABSTRACT

Introduction

Around 30% of patients with epilepsy suffer from drug-resistant seizures. Drug-resistant seizures may have significant consequences such as sudden death in epilepsy, injuries, memory disturbances, and childhood learning and developmental problems. Available antiepileptic drugs (AEDs) work via numerous mechanisms – mainly through inhibition of voltage-operated Na⁺ and/or Ca²⁺ channels, excitation of K⁺ channels, enhancement of GABA-mediated inhibition and/or blockade of glutamate-produced excitation. However, the discovery and development of novel brain targets may improve the future pharmacological management of epilepsy and hence is of pivotal importance.

Areas covered

This article examines novel drug targets such as brain multidrug efflux transporters and inflammatory pathways; it progresses to discuss possible strategies for the management of drug-resistant seizures. Reduction of the consequences of blood brain barrier dysfunction and enhancement of anti-oxidative defense are discussed.

Expert Opinion

Novel drug targets comprise brain multidrug efflux transporters, TGF-β, Nrf2-ARE or m-TOR signaling and inflammatory pathways. Gene therapy and antagomirs seem the most promising targets. Epileptic foci may be significantly suppressed by viral-vector-mediated gene transfer, leading to an increased in situ concentration of inhibitory factors (for instance, galanin). Also, antagomirs offer a promising possibility of seizure inhibition by silencing micro-RNAs involved in epileptogenesis and possibly in seizure generation.

KEYWORDS:

• Antiepileptic drugs
• epilepsy
• epileptogenesis
• pharmacoresistance
• seizures
• gene therapy
• antagomirs
• multidrug efflux transporters
• inflammatory pathways

Article highlights

• Pharmacological treatment of epilepsy with antiepileptic drugs can sufficiently control about 30% of patients. Uncontrolled patients suffer from drug-resistant epilepsy.

• Discovery of novel brain targets is expected to increase the efficacy of pharmacological management of epilepsy.

• Pharmacological targeting of brain multidrug efflux transporters, inflammatory pathways, TGF-β signaling, Nrf2-ARE signaling or m-TOR pathways is under investigation.

• Gene therapy (with the use of viral vectors) may provide an increased concentration of endogenous anticonvulsant agents in epileptic foci.

• Antagomirs, due to their antiepileptogenic and anticonvulsant effects, may prove valuable drugs by modifying the course of epilepsy and management of drug-resistant seizures.

• Considering the preclinical background and initial clinical experience, gene therapy and silencing relevant microRNAs with antagomirs seem the most promising methods for future management of epilepsy.

• Clinical evaluation of ligands (probably as an add-on therapy) may start soon with approved non-antiepileptic drugs (anakinra, everolimus, losartan, minocycline) or dietary supplements (resveratrol, sulforaphane) and fenfluramine which has been already registered for the management of Dravet syndrome.

This box summarizes key points contained in the article.

Declaration of interest

S.J. C. has received financial support from Bayer, GlaxoSmithKline, Janssen, Novartis, Sanofi-Aventis for lecturing. He was also a recipient of an unrestricted grant from GlaxoSmithKline.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper is not funded