title: Anticonvulsant activity of GABA uptake inhibitors and their prodrugs following central or systemic administration.
abstract: The activity of compounds inhibiting neuronal or glial GABA uptake has been assessed following intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) administration in DBA/2 mice (sound-induced seizures) or Swiss S mice (pentylenetetrazol-induced seizures). Sound-induced seizures are suppressed by the i.c.v. injection of (+/-)-nipecotic acid, 3.2 mumol, or (+/-)-cis-4-hydroxynipecotic acid, 2 mumol, but not by i.p. injection of (+/-)-nipecotic acid, 3.2 mmol/kg or (+/-)-cis-4-hydroxynipecotic acid 4 mmol/kg. Pentylenetetrazol-induced seizures are not suppressed by i.c.v. injection of (+/-)-nipecotic acid 1-4 mumol, or (+/-)-cis-4-hydroxynipecotic acid, 2-4 mumol. THPO (4,5,6,7-tetrahydroisoxazolo[4.5-c]pyridin-3-ol), 1-5 mumol i.c.v. or 1-4 mmol/kg i.p., protects against sound-induced seizures. There is no protection against pentylenetetrazol seizures after i.c.v. THPO injection, but THPO, 2-8 mmol/kg i.p., is protective. Among prodrugs, (+/-)-nipecotic acid pivaloyloxymethyl ester protects against sound-induced seizures, when given i.c.v. (3.2 mumol) or i.p. (1.6-3.2 mmol/kg) and against pentylenetetrazol seizures when given i.p. (0.5-4 mmol/kg). (+/-)-cis-4-hydroxynipecotic acid methyl ester protects against sound-induced seizures when given i.p. (3.2 mmol/kg), but is only partially protective against pentylenetetrazol seizures, when given i.p. (4 mmol/kg). Some prodrugs induce myoclonus following either i.c.v. or i.p. administration.
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D005260:Female; D018756:GABA Antagonists; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D009557:Nipecotic Acids / Q000494:pharmacology; D010433:Pentylenetetrazole; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D018756:GABA Antagonists; D007555:Isoxazoles; D009557:Nipecotic Acids; C026804:4,5,6,7-tetrahydroisoxazolo(4,5-c)pyridin-3-ol; D005680:gamma-Aminobutyric Acid; D010433:Pentylenetetrazole