T-Type Calcium Channel Blockers That Attenuate Thalamic Burst Firing and Suppress Absence Seizures

Abstract

Absence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanying spike-and-wave discharges on an electroencephalogram. They arise from abnormal, hypersynchronous neuronal firing in brain thalamocortical circuits. Currently available therapeutic agents are only partially effective and act on multiple molecular targets, including γ-aminobutyric acid (GABA) transaminase, sodium channels, and calcium (Ca(2+)) channels. We sought to develop high-affinity T-type specific Ca(2+) channel antagonists and to assess their efficacy against absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. Using a rational drug design strategy that used knowledge from a previous N-type Ca(2+) channel pharmacophore and a high-throughput fluorometric Ca(2+) influx assay, we identified the T-type Ca(2+) channel blockers Z941 and Z944 as candidate agents and showed in thalamic slices that they attenuated burst firing of thalamic reticular nucleus neurons in GAERS. Upon administration to GAERS animals, Z941 and Z944 potently suppressed absence seizures by 85 to 90% via a mechanism distinct from the effects of ethosuximide and valproate, two first-line clinical drugs for absence seizures. The ability of the T-type Ca(2+) channel antagonists to inhibit absence seizures and to reduce the duration and cycle frequency of spike-and-wave discharges suggests that these agents have a unique mechanism of action on pathological thalamocortical oscillatory activity distinct from current drugs used in clinical practice.

Pacemaker Neurons and Neuronal Networks in Health and Disease

“…From a clinical point of view, it has been reported that an increase during wakefulness of the bursting mode of RTN neurons is related to the generation of absence seizures [27,28]. Accordingly, absence seizures are successfully treated with T-type Ca2+ channel blockers such as ethosuximide, which reduces the bursting mode of RTNs [28,29].…”

A Cav3.2/Stac1 molecular complex controls T-type channel expression at the plasma membrane

“…20 In addition, up-regulation of T-type channels is responsible for epileptic seizures in several rodent models of epilepsy. [21][22][23][24][25][26] Although a number of signaling pathways regulating T-type channel activity have been reported, 27 the molecular mechanisms and signaling molecules controlling the trafficking, sorting, and expression of the channel protein at the plasma membrane remain largely unknown.…”

The Triggle effect

“…Particularly impressive from these efforts was the high degree of selectivity that the T-type blockers exhibited over other types of voltage-gated ion channels (e.g., Z944 shows >100 fold higher affinity to T-type channels compared to the N-type calcium channel, >500 fold compared to the L-type calcium channel and between 80 to 100 fold selectivity over voltage-gated sodium and potassium channels) [31].…”

“…The Triggle-Mitscher-imbued rational design strategy also drove NeuroMed's (by then renamed Zalicus Pharmaceuticals) generation of the first small organic pure T-type calcium channel blockers, Z941 and Z944, one of which has exhibited promising efficacy in both animal models of epilepsy and in a human model of experimental pain [29][30][31]. Indeed, derivation of the novel T-type blockers utilized the Z160 core towards further directed SAR (Fig.…”