Epilepsy: Novel therapeutic targets

Abstract

Despite of established and effective therapy for epilepsy, 20-25% patients develop therapeutic failure; this encourages finding newer drugs. Novel approaches target receptors which remain unaffected by conventional therapy or inhibit epileptogenesis. AMPA receptor antagonists have shown faster and complete protection compared to diazepam. Protein kinase (PK) plays an important role in the development of epilepsy. PK inhibitors such as K252a, VID-82925, and Herbimycin A have been found effective in inhibition of spread of epileptiform activity and epileptogenesis. Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors classified into three groups. Group 1 mGluRs antagonist and Groups 2 and 3 mGluRs agonists inhibited pentylenetetrazole-induced kindled seizures. Combined use of these agents has also shown favorable results. Mammalian target of rapamycin (mTOR) plays a central role in multiple mechanisms of epileptogenesis. mTOR causes transcription, induction of proapoptotic proteins, and autophagy inhibition. Rapamycin was effective in suppression of recurrent seizures as well as in tuberous sclerosis and acute brain injury model. 5% CO(2) showed potent effects on cortical epileptiform activity and convulsions in animal epilepsy models and in humans with drug-resistant partial epilepsy. It is found to be rapidly acting, safe and cheap, thus it can be a good option in emergency for suppression of seizure. Neurosteroids are considered as fourth generation neuromessengers, they act as positive allosteric modulators of γ-aminobutyric acid (GABAA) receptors. Clinical trial of ganaxolone, an allopregnanolone analogue, has shown a beneficial role in pharmacoresistant epilepsy. However, most of these drugs are tested in early phases of development and the possible use and safety in epilepsy has to be proven in clinical trials.

Keywords: AMPA receptor antagonists; mammalian target of rapamycin; metabotropic glutamate receptors; pharmacoresistant epilepsy; protein kinase inhibitors.

Figure 1

Role of a mammalian target of the rapamycin pathway in epileptogenesis