New Horizons in the development of antiepileptic drugs: Innovative strategies

Abstract

The past decades have brought many advances to the treatment of epilepsy. However, despite the continued development and release of new antiepileptic drugs, many patients have seizures that do not respond to drug therapy or have related side effects that preclude continued use. Even in patients in whom pharmacotherapy is efficacious, current antiepileptic drugs do not seem to affect the progression or the underlying natural history of epilepsy. Furthermore, there is currently no drug available which prevents the development of epilepsy, e.g. after head trauma or stroke. Thus, there are at least four important goals for the future: (1) development of better antiepileptic ("anti-ictal") drugs with higher efficacy and tolerability to stop seizures compared to current medications; (2) better understanding of processes leading to epilepsy, thus allowing to create therapies aimed at the prevention of epilepsy in patients at risk; (3) development of disease-modifying therapies, interfering with progression of epilepsy, and (4) improved understanding of neurobiological mechanisms of pharmacoresistance, allowing to develop drugs for reversal or prevention of drug resistance. The third Workshop on New Horizons in the Development of Antiepileptic Drugs explored these four goals for improved epilepsy therapy, with a focus on innovative strategies in the search for better anti-ictal drugs, for novel drugs for prevention of epilepsy or its progression, and for drugs overcoming drug resistance in epilepsy. In this conference review, the current status of antiepileptic therapies under development is critically assessed, and innovative approaches for future therapies are highlighted.

Figure 1

Model synapse illustrating interaction of Na⁺ channel blocking AEDs with voltage-activated Na⁺ channels and putative sites of action of newer AEDs that may more directly interact with release machinery. Gabapentin and pregabalin bind to α₂-δ, which may inhibit voltage-activated Ca²⁺ entry through high voltage-activated Ca²⁺ channels or affect the way in which Ca²⁺ channels interact with vesicular release. Levetiracetam may also affect release by binding to synaptic vesicles protein SV2A. Action potentials are mediated by voltage-activated Na⁺ and K⁺ channels; Na⁺ channel blocking AEDs suppress epileptiform action potential firing, which leads to inhibited release. Small blue circles indicate ions; larger yellow circles represent glutamate within synaptic vesicles and free in the synaptic cleft. Glutamate acts on ionotropic receptors (of the NMDA, AMPA and kainate types) to generate an excitatory postsynaptic potential (EPSP) in the postsynaptic neuron.

Figure 2

Relationship between α₂-δ binding affinity, system L transporter affinity, and potency for protection against audiogenic seizures in DBA/2 mice for gabapentin, pregabalin and structural analogs. The Y-axis represents the percent protection (out of 5 animals) in the seizure model at a dose of 30 mg/kg, p.o. The Z-axis represents the concentration (μM) producing half-maximal inhibition of [³H]L-leucine uptake by the system L transporter in CHO-K1 cells. The X-axis represents the concentration (μM) producing half-maximal inhibition of specific [³H]gabapentin binding to pig brain membranes. Seizure protection correlates with α₂-δ binding only for those compounds that are substrates for the system L transporter, which appears to be required for absorption by the gut and delivery to the brain (D.J. Wustrow and C.P. Taylor, unpublished).