Z944, a Novel Selective T-Type Calcium Channel Antagonist Delays the Progression of Seizures in the Amygdala Kindling Model.
Temporal lobe epilepsy (TLE) is the most common form of drug resistant epilepsy. Current treatment is symptomatic, suppressing seizures, but has no disease modifying effect on epileptogenesis. We examined the effects of Z944, a potent T-type calcium channel antagonist, as an anti-seizure agent and against the progression of kindling in the amygdala kindling model of TLE. The anti-seizure efficacy of Z944 (5mg/kg, 10mg/kg, 30mg/kg and 100mg/kg) was assessed in fully kindled rats (5 class V seizures) as compared to vehicle, ethosuximide (ETX, 100mg/kg) and carbamazepine (30mg/kg). Each animal received the seven treatments in a randomised manner. Seizure class and duration elicited by six post-drug stimulations was determined. To investigate for effects in delaying the progression of kindling, naive animals received Z944 (30mg/kg), ETX (100mg/kg) or vehicle 30-minutes prior to each kindling stimulation up to a maximum of 30 stimulations, with seizure class and duration recorded after each stimulation. At the completion of drug treatment, CaV3.1, CaV3.2 and CaV3.3 mRNA expression levels were assessed in the hippocampus and amygdala using qPCR. Z944 was not effective at suppressing seizures in fully kindled rats compared to vehicle. 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. There was no significant difference in the mRNA expression of the T-type Ca2+ channels in the hippocampus or amygdala. Our results show that selectively targeting T-type Ca2+ channels with Z944 inhibits the progression of amygdala kindling. This could be a potential for a new therapeutic intervention to mitigate the development and progression of epilepsy.
The Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia.
Pablo Miguel
PM
Casillas-Espinosa
The Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia.
Ashleigh
A
Hicks
The Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia.
Amy
A
Jeffreys
Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.
Terrance P
TP
Snutch
The Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia.
Terence J
TJ
O'Brien
The Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia.
Kim L
KL
Powell
D000081:Acetamides; D000679:Amygdala / Q000187:drug effects / Q000473:pathology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D007696:Kindling, Neurologic / Q000187:drug effects*; D010880:Piperidines; D051381:Rats; D012640:Seizures / Q000188:drug therapy*
D000081:Acetamides; D000927:Anticonvulsants; D001549:Benzamides; D002121:Calcium Channel Blockers; D010880:Piperidines; C000629485:Z944