Pharmacological evidence that alpha-ketoisovaleric acid induces convulsions through GABAergic and glutamatergic mechanisms in rats.

Abstract

Neurological dysfunction is common in patients with maple syrup urine disease (MSUD). However, the mechanisms underlying the pathophysiology of this disorder are poorly known. In the present study we investigated the effect of intrastriatal administration of the alpha-keto acids accumulating in MSUD on the behavior of adult rats. After cannula placing, rats received unilateral intrastriatal injections of alpha-ketoisocaproic acid (KIC, 8 micromol), alpha-ketoisovaleric acid (KIV, 8 micromol), alpha-keto-beta-methylvaleric acid (KMV, 6 micromol) or NaCl. KIV elicited clonic convulsions in a dose-response manner, whereas KIC and KMV did not induce seizure-like behavior. Convulsions provoked by KIV were prevented by intrastriatal preadministration of muscimol (46 pmol) and MK-801 (3 nmol), but not by the preadministration of DNQX (8 nmol). These results indicate that among the keto acids that accumulate in MSUD, KIV is the only metabolite capable of causing convulsions in the present animal model and indicates that KIV is an important excitatory metabolite. Moreover, the participation of GABAergic and glutamatergic NMDA mechanisms in the KIV-induced convulsant behavior is suggested, since KIV-induced convulsions are attenuated by muscimol and MK-801. The authors suggest that KIV may play an important role in the convulsions observed in MSUD, and highlight its relevance to the understanding of the pathophysiology of the neurological dysfunction of MSUD patients.

• Authors: A S Coitinho, C F de Mello, T T Lima, J de Bastiani, M R Fighera, M Wajner
• Journal: Brain research (Brain Res) Vol. 894 Issue 1 Pg. 68-73 (Mar 09 2001) ISSN: 0006-8993 [Print] Netherlands
• PMID: 11245816 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Excitatory Amino Acid Antagonists
• GABA Agonists
• Hemiterpenes
• Keto Acids
• Receptors, GABA
• Receptors, N-Methyl-D-Aspartate
• alpha-keto-beta-methylvaleric acid
• alpha-ketoisovalerate
• alpha-ketoisocaproic acid

Topics

• Animals
• Corpus Striatum (drug effects, metabolism)
• Excitatory Amino Acid Antagonists (pharmacology, therapeutic use)
• GABA Agonists (pharmacology, therapeutic use)
• Hemiterpenes
• Keto Acids (adverse effects)
• Male
• Maple Syrup Urine Disease (metabolism)
• Rats
• Rats, Wistar
• Receptors, GABA (drug effects, metabolism)
• Receptors, N-Methyl-D-Aspartate (drug effects, metabolism)
• Seizures (chemically induced, drug therapy)