The gamma-aminobutyric acid uptake inhibitor, tiagabine, is anticonvulsant in two animal models of reflex epilepsy.

Abstract

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.

• Authors: S E Smith, N S Parvez, A G Chapman, B S Meldrum
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 273 Issue 3 Pg. 259-65 (Feb 06 1995) ISSN: 0014-2999 [Print] Netherlands
• PMID: 7737333 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• GABA Agents
• Neurotransmitter Uptake Inhibitors
• Nicotinic Acids
• Nipecotic Acids
• Oximes
• NNC 711
• nipecotic acid
• Carbamazepine
• Proline
• homoproline
• Tiagabine

Topics

• Acoustic Stimulation
• Animals
• Anticonvulsants (pharmacology)
• Behavior, Animal (drug effects)
• Carbamazepine (pharmacology)
• Epilepsy (drug therapy, genetics, physiopathology)
• Female
• GABA Agents (pharmacology)
• Male
• Motor Activity (drug effects)
• Myoclonus (drug therapy, genetics)
• Neurotransmitter Uptake Inhibitors (pharmacology)
• Nicotinic Acids (pharmacology)
• Nipecotic Acids (pharmacology)
• Oximes (pharmacology)
• Papio
• Photic Stimulation
• Proline (analogs & derivatives)
• Rats
• Rats, Inbred Strains
• Tiagabine