High anticonvulsant potency of gamma-aminobutyric acid (GABA)mimetic drugs in gerbils with genetically determined epilepsy.
Seven GABAmimetic drugs, namely cetyl gamma-aminobutyric acid (cetyl GABA), 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol, progabide, aminooxyacetic acid, alpha-acetylenic GABA, (-)-nipecotic acid ethyl ester and (+/-)-cis-4-hydroxynipecotic acid methyl ester, were tested for their potency to block "major" (generalized clonic-tonic) seizures in gerbils, induced by blowing at the animals with compressed air. Valproic acid was included as a reference standard. All drugs proved able to protect gerbils from induced seizures. Most effective were 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol (ED50, 1.3 mg/kg i.p.), aminooxyacetic acid (0.9), cetyl GABA (4.5) and gamma-acetylenic GABA (2.1). A comparison with anticonvulsant ED50 values of common antiepileptics in the gerbil showed that these four GABAmimetics were clearly more potent than phenobarbital, phenytoin, carbamazepine, ethosuximide and valproic acid and were only surpassed in potency by diazepam. Furthermore, most GABAmimetics proved strikingly more active in the gerbil compared with the classical electroshock and pentylenetetrazol seizure models in mice. After administration of gamma-acetylenic GABA, GABA increases in the brain of only about 40% were found sufficient to reach almost complete seizure protection in gerbils. The present data are compatible with the possibility that the GABA system is critically involved in the seizure-prone state in the gerbil.
D000480:Alkynes; D000614:Aminocaproates / Q000008:administration & dosage; D000625:Aminooxyacetic Acid / Q000008:administration & dosage; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000494:pharmacology; D003975:Diazepam / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005849:Gerbillinae; D007555:Isoxazoles / Q000008:administration & dosage; D008297:Male; D051379:Mice; D012640:Seizures / Q000188:drug therapy*; D014635:Valproic Acid / Q000008:administration & dosage; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000494:pharmacology
D000480:Alkynes; D000614:Aminocaproates; D000927:Anticonvulsants; D007555:Isoxazoles; D000625:Aminooxyacetic Acid; C006510:gamma-aminobutyric acid cetyl ester; D005680:gamma-Aminobutyric Acid; C013785:4-amino-5-hexynoic acid; D014635:Valproic Acid; C015542:gaboxadol; D003975:Diazepam