Anticonvulsant effects of the 3-hydroxyanthranilic acid dioxygenase inhibitor NCR-631.
The kynurenine pathway intermediate 3-hydroxyanthranilic acid (3-HANA) is converted by 3-HANA 3,4-dioxygenase (3-HAO) to the pro-convulsive excitotoxin quinolinic acid. In the present study, the anticonvulsant effect of the 3-HAO inhibitor NCR-631 was investigated in models of chemically- and sound-induced seizures. Administration of NCR-631 i.c.v. at a dose of 300nmol in Sprague-Dawley rats was found to prolong the latency of occurrence of pentylenetetrazole (PTZ)-induced seizures. Also systemic pre-treatment with NCR-631 s.c. in N.M.R.I. mice subjected to PTZ-induced seizures provided an increase in the latency until onset of seizures, concomitant with a reduction in the severity of the seizures. However, the anticonvulsant effect of NCR-631 was short lasting (15-30min), and only observed at a dose of 250 mg/kg. A similar dose- and time-dependent anticonvulsant effect of NCR-631 was found in seizure-prone DBA/2J mice following sound-induced convulsions. Hence, the findings show that NCR-631 has anticonvulsant properties against generalized tonic-clonic seizures of different origin, suggesting that it may constitute a useful tool to study the role of kynurenines in various convulsive states.
Luthman
J
J
Department of Bioscience, AstraZeneca R&D Södertälje, Sweden.
D015095:3-Hydroxyanthranilic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control
C104255:4,6-dibromo-3-hydroxyanthranilic acid; D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D015095:3-Hydroxyanthranilic Acid