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

点击翻译按钮获取中文摘要

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.