The gamma-aminobutyric acid uptake inhibitor, tiagabine, is anticonvulsant in two animal models of reflex epilepsy.
The effects of i.p. administration of the gamma-aminobutyric acid (GABA) uptake inhibitors R(-)N-(4,4-di(3-methylthien-2-yl)-but-3-enyl) nipecotic acid hydrochloride (tiagabine; molecular weight 412.0), (1-(2-(((diphenylmethylene)-amino)oxy)ethyl)-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride (NNC-711; molecular weight 386.9), and (+/-)-nipecotic acid (molecular weight 128.2) are compared with those of carbamazepine (molecular weight 236.3) on sound-induced seizures and locomotor performance in genetically epilepsy-prone (GEP) rats. The ED50 value against clonic seizures (in mumol kg-1 at the time of maximal anticonvulsant effect) for tiagabine was 23 (0.5 h), and for NNC-711 was 72 (1 h), and for carbamazepine was 98 (2 h). (+/-)-Nipecotic acid (0.4-15.6 mmol kg-1) was not anticonvulsant. High doses of NNC-711 (207-310 mumol kg-1) and of (+/-)-nipecotic acid (39-78 mmol kg-1) induced ataxia and myoclonic seizures 0.25-1 h. Tiagabine and carbamazepine did not induce myoclonic seizures and had similar therapeutic indices (locomotor deficit ED50/anticonvulsant ED50) ranging from 0.4 to 1.9. In Papio papio, we observed a reduction in photically induced myoclonic seizures with tiagabine (2.4 mumol kg-1 i.v.) accompanied with neurological impairment. Tiagabine has comparable anticonvulsant action to carbamazepine in rats and has anticonvulsant effects in non-human primates supporting the potential use of inhibitors of GABA uptake as therapy for epilepsy.
Smith
S E
SE
Department of Neurology, Institute of Psychiatry, De Crespigny Park, London, UK.
Parvez
N S
NS
Chapman
A G
AG
Meldrum
B S
BS
D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002220:Carbamazepine / Q000494:pharmacology; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D005260:Female; D018682:GABA Agents / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009207:Myoclonus / Q000188:drug therapy / Q000235:genetics; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009539:Nicotinic Acids / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology*; D010091:Oximes / Q000494:pharmacology; D010215:Papio; D010775:Photic Stimulation; D011392:Proline / Q000031:analogs & derivatives*; D051381:Rats; D011919:Rats, Inbred Strains; D000078308:Tiagabine
D000927:Anticonvulsants; D018682:GABA Agents; D014179:Neurotransmitter Uptake Inhibitors; D009539:Nicotinic Acids; D009557:Nipecotic Acids; D010091:Oximes; C078793:NNC 711; C030278:nipecotic acid; D002220:Carbamazepine; D011392:Proline; C010983:homoproline; D000078308:Tiagabine