ROLE OF MALATE, LACTATE, AND ALANINE IN BRAIN METABOLISM AND TRAFFICKING

我们假设支链氨基酸水平升高 枫叶患者脑组织中α-酮酸的含量 糖浆尿病(MSUD)改变了氨基酸的释放和吸收， 影响大脑的能量代谢，扰乱正常的细胞间 运输，并通过参与氨基酸的酶改变通量 神经递质合成。BCAA和BCKA对 谷氨酸、谷氨酰胺和天冬氨酸在脑内的合成 作为氮素供体或受体。这些扰动可能会导致 谷氨酸、GABA和天冬氨酸显著下降 MSUD患者尸检时的大脑。谷氨酸水平的变化 与其相关的氨基酸与急性和长期的 迟发性神经元损伤和脑功能异常。大型船舶的运输 大脑中的中性氨基酸也可能受到影响，因为它们共享一种 支链氨基酸共同携带者。体内实验的主要目标之一是 微透析研究是为了建立支链氨基酸和支链氨基酸的作用机制 改变大鼠脑灌流间质氨基酸水平的实验研究 使用BCAA或BCKA。在那里，这些研究将在#年并行进行。 完整的大鼠脑和培养的脑细胞。第二个目标是 在体微透析研究是为了测量支链氨基酸和支链氨基酸的作用 葡萄糖、谷氨酸和谷氨酰胺的氧化代谢。我们有 在体内证明了和α-酮基异己酸酯刺激葡萄糖， 谷氨酸和谷氨酰胺氧化。后者正在由一个 微渗析技术在局部氧化检测中的创新应用 葡萄糖和替代脑底物，在完整的大鼠大脑中减少到14CO2。 竞争底物、脑区和MSUD代谢物对 将对底物氧化进行分析，以确定 个别底物的氧化代谢。活体微透析 结果将与培养的星形胶质细胞的平行研究进行比较， 皮质神经元、小脑颗粒细胞和混合细胞培养。 拟议的研究将探索超标的机制 BCAA和BCKA在细胞水平上影响大脑功能，从而 损害了正常的精神发育。这些研究的结果 应提供有关MSUD病因的有价值的信息，并提供 这种情况的临床治疗指南。

We hypothesize that elevated levels of branched chain amino acids (BCAA) and their alpha-keto acids (BCKA) in the brain of patients with Maple Syrup Urine Disease (MSUD) alters the release and up take of amino acids, affects energy metabolism of the brain, disrupts normal intercellular trafficking, and alters the flux through enzymes involved in amino acid neurotransmitter synthesis. BCAA and BCKA have a direct effect on the synthesis of glutamate, glutamine and aspartate in brain by their action as a nitrogen donor or acceptor. These perturbations may result in the pronounced decrease of glutamate, GABA, and aspartate reported in the brain of MSUD patients at autopsy. Alterations in the levels of glutamate and its related amino acids have been associated with both acute and long term neuronal damage and abnormal brain function. Transport of large neutral amino acids in brain may also be affected since they share a common carrier with BCAA. One of the major goals of the in vivo microdialyis studies is to establish the mechanisms by which BCAA and BCKA alter the level of amino acids in the interstitial space of rats perfused with BCAA or BCKA. There, these studies will be performed in parallel in the intact rat brain and in cultured brain cells. The second goal of the in vivo micro dialysis studies is to measure the effects of BCAA and BCKA on the oxidative metabolism of glucose, glutamate and glutamine. We have demonstrated in vivo that and alpha-ketoisocaproate stimulates glucose, glutamate and glutamine oxidation. The latter is being studied by an innovative adaptation of microdialysis to measure focal oxidation of glucose, and alternate brain substrates, to 14CO2 in the intact rat brain. The effect of competing substrates, brain region, and MSUD metabolites on substrate oxidation will be analyzed to determine the compartmentation of oxidative metabolism for individual substrates. The in vivo micro dialysis results will be compared to parallel studies in cultured astrocytes, cortical neurons, cerebellar granule cells, and in mixed cell cultures. The proposed studies will explore the mechanisms by which excessive levels of BCAA and BCKA affect brain function at the cellular level, thereby compromising normal mental development. The results of these studies should provide valuable information about the etiology of MSUD and provide guidelines for clinical approaches to this condition.