LARGE NEUTRAL AMINO ACIDS--TRANSPORT AND EFFECTS ON OXIDATIVE BRAIN METABOLISM

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) perturb not only amino acid transport, but also affect brain energy metabolism, disrupt the equilibrium of intercellular trafficking, and alter flux through enzymes involved in amino acid neurotransmitter synthesis. Ultimately such perturbations may have profound effects on neurodevelopment leading to mental retardation. Four recent findings from our laboratory support this hypothesis: 1) elevated levels of alpha-ketoisocaproate (alpha-KIC) introduced via microdialysis stimulate the in vivo oxidation of glutamate and glutamine, altering the energy states of the cells and decreasing the availability of glutamate for neurotransmitter function; 2) we have demonstrated in the intact brain that the oxidative metabolism of glutamate and glutamine is compartmentalized with glutamine oxidation rates in the hippocampus being approximately 5-fold greater than glutamate oxidation rates; 3) elevated levels of leucine and alpha-KIC, introduced via microdialysis to the interstitial space of rat brain, result in a 2-4 fold increase in the interstitial concentrations of large neutral amino acids (LNAA) and glutamine and 4) cultured rat cortical neurons and astrocytes have a pronounced different intracellular response to exogenous BCAA and BCKA. The proposed studies will: 1) combine two established methodologies, i.e., microdialysis and specific cellular ablation, to determine the effect of BCAA and BCKA on the oxidative metabolism by specific cell types in different brain regions; 2) determine the effect of BCAA and BCKA on amino acid exchanges into the interstitial fluid following ablation of specific types of brain cells by neurotoxic compounds; 3) characterize transport of LNAA by neuronal cells; 4) characterize the effect of LNAA and BCKA on glutamate/glutamine metabolism in the intact rat brain and in culture brain cells of know cell type. Inclusion of human astrocytes, normal and trisomic 21, should provide valuable information about the etiology of mental retardation resulting from in born errors of metabolism and chromosomal abnormalities and will provide guidelines for clinical approaches to these conditions.