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

Neurological dysfunction is common in patients with maple syrup urine disea se (MSUD). However, the mechanisms underlying; the pathophysiology of this disorder are poorly known. Ln the present study we investigated the effect of intrastriatal administration of the alpha -keto acids accumulating in MS UD on the behavior of adult rats. After cannula placing, rats received unil ateral intrastriatal injections of alpha -ketoisocaproic acid (KIC, 8 mu mo l), alpha -ketoisovaleric acid (KIV, 8 mu mol), alpha -keto-beta -methylval eric acid (KMV, 6 mu mol) or NaCl. KIV elicited clonic convulsions in a dos e-response manner, whereas KIC and KMV did not induce seizure-like behavior . Convulsions provoked by KIV were prevented by intrastriatal preadministra tion of muscimol (46 pmol) and MK-801 (3 nmol), but not by the preadministr ation of DNQX (8 nmol). These results indicate that among the keto acids th at accumulate in MSUD, KIV is the only metabolite capable of causing convul sions in the present animal model and indicates that KIV is an important ex citatory metabolite. Moreover, the participation of GABAergic and glutamate rgic NMDA mechanisms in the KIV-induced convulsant behavior is suggested, s ince KIV-induced convulsions are attenuated by muscimol and MK-801. The aut hors suggest that KIV may play an important role in the convulsions observe d in MSUD, and highlight its relevance to the understanding of the pathophy siology of the neurological dysfunction of MSUD patients. (C) 2001 Elsevier Science B.V. All rights reserved.