Anticonvulsant activity of GABA uptake inhibitors and their prodrugs following central or systemic administration.

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.