Coitinho A S, de Mello C F, Lima T T, de Bastiani J, Fighera M R, Wajner M
Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Departamento de Bioquímica, Rua Ramiro Barcelos 2600, RS 90035-003, Porto Alegre, Brazil.
Brain Res. 2001 Mar 9;894(1):68-73. doi: 10.1016/s0006-8993(00)03321-7.
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.
枫糖尿症（MSUD）患者常出现神经功能障碍。然而，这种疾病病理生理学的潜在机制却鲜为人知。在本研究中，我们调查了纹状体内注射MSUD中蓄积的α-酮酸对成年大鼠行为的影响。插管后，大鼠接受单侧纹状体内注射α-酮异己酸（KIC，8微摩尔）、α-酮异戊酸（KIV，8微摩尔）、α-酮-β-甲基戊酸（KMV，6微摩尔）或氯化钠。KIV以剂量反应方式引发阵挛性惊厥，而KIC和KMV未诱发类似癫痫发作的行为。纹状体内预先注射蝇蕈醇（46皮摩尔）和MK-801（3纳摩尔）可预防KIV引发的惊厥，但预先注射DNQX（8纳摩尔）则不能。这些结果表明，在MSUD中蓄积的酮酸中，KIV是目前动物模型中唯一能够引起惊厥的代谢产物，这表明KIV是一种重要的兴奋性代谢产物。此外，由于蝇蕈醇和MK-801可减轻KIV诱导的惊厥，提示GABA能和谷氨酸能NMDA机制参与了KIV诱导的惊厥行为。作者认为KIV可能在MSUD中观察到的惊厥中起重要作用，并强调其与理解MSUD患者神经功能障碍病理生理学的相关性。
