Abstracts

Rationale: Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults that is refractory to medical treatment. Current therapeutic treatment is symptomatic, suppressing seizures, but has no disease modifying effect on epileptogenesis. T-type Ca2+ channels have been implicated in pathogenesis of limbic epilepsy, therefore the current study set out to investigate the effects of a novel T-type Ca2+ channel antagonist (Z944) on the progression of epileptogenesis and the treatment of seizures in the amygdala kindling model of TLE.Methods: All female Wistar rats underwent surgery to implant a bipolar electrode into the left amygdala for electrical kindling stimulation as well as subdural electroencephalogram (EEG) recording electrodes. The anti-epileptic efficacy of Z944 was determined in fully kindled rats (five class V seizures, n=7). Z944 (5mg/kg, 10mg/kg, 30mg/kg and 100mg/kg), vehicle (0.5% Na-CMC in DMSO), ethosuximide (ETX, 100mg/kg) and carbamazepine (30mg/kg) were administered ip and 6 post-drug stimulations were given starting 15 min after drug administration. Each animal received each of the 7 treatments in a randomised manner. For the anti-epileptogenesis study, animals received Z944 (30mg/kg) (n=7), ETX (100mg/kg) (n=6) or vehicle (0.5% Na-CMC in DMSO, n=6) 30 minutes prior to each kindling stimulation up to a maximum of 30 stimulations. Animals were monitored for neurotoxicity and sedation for the entire treatment period. EEGs were analysed in a blinded manner and the kindled seizure class, primary and total seizure duration were determined. For molecular analysis, mRNA expression levels were assessed in the hippocampus and amygdala using qPCR for Cav3.1, total Cav3.2, Cav3.2 +/- exon 25 splice variants, and Cav3.3.Results: Z944 was not effective at suppressing seizures in fully kindled rats. Z944 significantly reduced seizure class at 100mg/kg (p<0.05) when compared to vehicle, but this was probably due to the neurotoxicity rather than a true anti-seizure effect. For the anti-epileptogenesis study, animals receiving Z944 required significantly more stimulations to evoke a class III (p<0.05), IV (p<0.01) or V (p<0.0001) seizure and to reach a fully kindled state (p<0.01) than animals receiving vehicle. Interestingly, only one Z944 treated animal reached the fully kindled state. There was no significant difference in Cav3.1, total Cav3.2, Cav3.2 +/- exon 25 splice variants, and Cav3.3 mRNA expression in the hippocampus and amygdala between the three treatment groups.Conclusions: These results provide evidence that T-type Ca2+ channels are important in development of limbic epileptogenesis and that drugs that target these channels may represent a new therapeutic intervention to prevent the progression of limbic epilepsy.