Exploring the latest avenues for antiepileptic drug discovery and development

ABSTRACT

Introduction: In about 30% of patients with epilepsy, seizures are not sufficiently controlled with the available antiepileptic medication. There is a need for newer drugs, not only aimed at suppressing seizure activity but for the efficient inhibition of epileptogenesis.

Areas covered: In this review, the authors consider different approaches for the management of drug-resistant epilepsy and various possible ways on how to stop epileptogenesis.

Expert opinion: There is limited evidence for antiepileptogenic effects of antiepileptic drugs. Post-status epilepticus animal models will probably help the discovery of antiepileptogenic compounds among already approved non-antiepileptic drugs or other agents. A good example is losartan, which significantly inhibits epileptogenesis in vivo. Some agents that affect the mTOR signaling system, or that inhibit the synthesis of the proconvulsant cytokine as well as those derived from plants (resveratrol) also seem effective in this regard. Furthermore, agonists of peroxisome proliferator-activated receptors have proven effective in some models of seizures but data on their possible antiepileptogenic activity is quite limited. In addition to the discovery of new antiepileptogenic and/or antiepileptic compounds, there is a possibility of improving the treatment of drug-resistant cases through the rational use of antiepileptic drug combinations.

KEYWORDS:

• Antiepileptic drugs
• epileptogenesis
• losartan
• rapamycin
• resveratrol
• seizures

Article highlights

• About 70% of patients with epilepsy are sufficiently controlled with conventional or newer antiepileptic drugs. However, the remaining 30% appear resistant to pharmacological treatment.

• Existing classical models of seizures, leading to the discovery of currently available antiepileptic drugs, may fail to delineate drugs effective against refractory epilepsies.

• Antiepileptogenic drugs, inhibiting the progression of epilepsy, could prove effective in prevention of drug resistant seizures. Post-status epilepticus models of temporal lobe epilepsy may be useful for identifying agents suppressing epileptogenesis.

• Some antiepileptic drugs can inhibit epileptogenesis reflected by suppression of remote, post-status epilepticus generated seizure activity. However, contradictory data exist on some antiepileptics (valproste) and the effects of some may be strictly protocol-dependent (diazepam).

• Post-status epilepticus models have so far identified already approved non-antiepileptic drugs (losartan, rapamycin) or plant-derived agents (resveratrol) as potent inhibitors of epileptogenesis. There is also some hope for agonists of peroxisome proliferator-activated receptors. Presumed antiepileptogenic effects of drugs or agents identified in post-status epilepticus models must be verified in clinical trials.

• So far, conventional antiepileptic drugs have failed to inhibit epileptogenesis in patients following traumatic brain injury. Also, they have been found ineffective in blocking epileptogenesis associated with brain tumor or febrile seizures. However, there is some hope for LEV, as an antiepileptic drug able to suppress remote epilepsy after traumatic brain injury.

Declaration of interest

The authors are supported by a grant from the Medical University of Lublin (grant no. DS 475/15) and a grant from the National Science Centre (grant no. 2013/09/B/NZ7/04010). Furthermore SJ Cruczwar has been a speaker for GlaxoSmithKline, Sanofi Aventis, UCB and Janssen Pharmaceuticals. Both he and J Luszczki have also both received unrestricted grants 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 apart from those disclosed.