Anticonvulsant effects of the 3-hydroxyanthranilic acid dioxygenase inhibitor NCR-631 |
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Authors: | J Luthman |
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Institution: | Department of Bioscience, AstraZeneca R&D S?dert?lje, Sweden, SE
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Abstract: | Summary. 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 300 nmol
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 (15–30 min), 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.
Received August 31, 1999 Accepted September 20, 1999 |
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Keywords: | : Amino acids Seizures Epilepsy Kynurenines Quinolinic acid |
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