Anticonvulsant activity of intracerebroventricularly administered glial GABA uptake inhibitors and other GABAmimetics in chemical seizure models.
The antiseizure activities of glial or neuronal GABA uptake inhibitors and GABA agonists were compared following intracerebroventricular administration in 2 acute models of chemoconvulsion in rats. The glia-selective GABA uptake inhibitor, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO), given at doses of 100-750 micrograms, i.c.v., protected against maximal pentylenetetrazol (PTZ) seizures and increased the latency to isonicotinic acid hydrazide (INH) seizures for at least 1 h following central administration. THPO failed to increase PTZ seizure thresholds. In contrast, the more potent partly glia-selective GABA uptake inhibitor, cis-4-hydroxynipecotic acid (30-300 micrograms), which is also a substrate for neuronal and glial transport systems, protected only 33% of rats against PTZ-induced tonic extension and had no effect on INH seizure latency. The neuron-selective uptake inhibitor L-2,4-diaminobutyric acid (DABA) at 1500 micrograms exhibited anti-PTZ activity initially and then, after a delay, produced proconvulsant behavior and spontaneous myoclonus in some animals. Intracerebroventricular injection of the GABA receptor agonist, muscimol, at toxic doses, gave rise to mixed anticonvulsant (INH seizures) and proconvulsant (PTZ seizure thresholds) effects. The results suggest that THPO, of the 4 compounds tested, possesses significant anticonvulsant activity. Its ability to suppress tonic but not generalized minor seizures suggests that it may block seizure spread.
Gonsalves
S F
SF
Department of Surgery, Dartmouth-Hitchcock Medical Center, Hanover, NH 03756.
Twitchell
B
B
Harbaugh
R E
RE
Krogsgaard-Larsen
P
P
Schousboe
A
A
D000613:Aminobutyrates / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D007538:Isoniazid; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000627:therapeutic use*; D009557:Nipecotic Acids / Q000627:therapeutic use*; D010080:Oxazoles / Q000627:therapeutic use*; D010433:Pentylenetetrazole; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000613:Aminobutyrates; D000927:Anticonvulsants; D007555:Isoxazoles; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; D010080:Oxazoles; C005959:2,4-diaminobutyric acid; C026804:4,5,6,7-tetrahydroisoxazolo(4,5-c)pyridin-3-ol; D005680:gamma-Aminobutyric Acid; C047022:4-hydroxynipecotic acid; D007538:Isoniazid; D010433:Pentylenetetrazole