Glutamic acid is an important excitatory neurotransmitter of the brain. Two key goals of brain amino acid handling are to maintain a very low intrasynaptic concentration of glutamic acid and also to provide the system with precursors from which to synthesize glutamate. The intrasynaptic glutamate level must be kept low to maximize the signal-to-noise ratio upon the release of glutamate from nerve terminals and to minimize the risk of excitotoxicity consequent to excessive glutamatergic stimulation of susceptible neurons. The brain must also provide neurons with a constant supply of glutamate, which both neurons and glia robustly oxidize. The branched-chain amino acids (BCAAs), particularly leucine, play an important role in this regard. Leucine enters the brain from the blood more rapidly than any other amino acid. Astrocytes, which are in close approximation to brain capillaries, probably are the initial site of metabolism of leucine. A mitochondrial branched-chain aminotransferase is very active in these cells. Indeed, from 30 to 50% of all alpha-amino groups of brain glutamate and glutamine are derived from leucine alone. Astrocytes release the cognate ketoacid [alpha-ketoisocaproate (KIC)] to neurons, which have a cytosolic branched-chain aminotransferase that reaminates the KIC to leucine, in the process consuming glutamate and providing a mechanism for the "buffering" of glutamate if concentrations become excessive. In maple syrup urine disease, or a congenital deficiency of branched-chain ketoacid dehydrogenase, the brain concentration of KIC and other branched-chain ketoacids can increase 10- to 20-fold. This leads to a depletion of glutamate and a consequent reduction in the concentration of brain glutamine, aspartate, alanine, and other amino acids. The result is a compromise of energy metabolism because of a failure of the malate-aspartate shuttle and a diminished rate of protein synthesis.
"At the BBB, elevated BCAAs may saturate the LAT-1 (see below) transporter and block uptake of other large neutral amino acids (LNAA; including phenylalanine (PHE), tyrosine (TYR), methionine (MET); tryptophan (TRP); and histidine (HIS)). Increased blood BCKAs enter the brain via the monocarboxylate transporter (MCT) and reverse flux through cerebral transaminases, depleting brain glutamate (GLU), glutamine (GLN) and gamma-aminobutyric acid (GABA) (among others), while enhancing production of LEU and α-ketoglutarate [5,22-25]. These disruptions in brain amino acid homeostasis may also be accompanied by disruptions of oxidative phosphorylation, elevated cerebral lactate level and oxidative damage [20,26]. "
[Show abstract][Hide abstract] ABSTRACT: Background
Conventional therapy for patients with maple syrup urine disease (MSUD) entails restriction of protein intake to maintain acceptable levels of the branched chain amino acid, leucine (LEU), monitored in blood. However, no data exists on the correlation between brain and blood LEU with protein restriction, and whether correction in blood is reflected in brain.
To address this question, we fed intermediate MSUD mice diets of 19% (standard) and 6% protein, with collection of sera (SE), striata (STR), cerebellum (CE) and cortex (CTX) for quantitative amino acid analyses.
LEU and valine (VAL) levels in all brain regions improved on average 28% when shifting from 19% to 6% protein, whereas the same improvements in SE were on average 60%. Isoleucine (ILE) in brain regions did not improve, while the SE level improved 24% with low-protein consumption. Blood-branched chain amino acids (LEU, ILE, and VAL in sera (SE)) were 362-434 μM, consistent with human values considered within control. Nonetheless, numerous amino acids in brain regions remained abnormal despite protein restriction, including glutamine (GLN), aspartate (ASP), glutamate (GLU), gamma-aminobutyric acid (GABA), asparagine (ASN), citrulline (CIT) and serine (SER). To assess the specificity of these anomalies, we piloted preliminary studies in hyperphenylalaninemic mice, modeling another large neutral aminoacidopathy. Employing an identical dietary regimen, we found remarkably consistent abnormalities in GLN, ASP, and GLU.
Our results suggest that blood amino acid analysis may be a poor surrogate for assessing the outcomes of protein restriction in the large neutral amino acidopathies, and further indicate that chronic neurotransmitter disruptions (GLU, GABA, ASP) may contribute to long-term neurocognitive dysfunction in these disorders.
"Leucine acts on an mTOR-dependent kinase that is non-insulin dependent, promotes anabolism of muscle tissue, maintains stable glucose levels, and lowers insulin during energy restriction . Leucine crosses the blood–brain barrier more rapidly than other amino acids , and its important role in hypothalamic regulation of food intake has been demonstrated in the recent studies . "
[Show abstract][Hide abstract] ABSTRACT: Whey proteins represent the most satiating nutrients. In particular, their effects are due to enterohormonal changes (CCK, GLP-1 and PYY 1–36) observed after their exclusive ingestion. Glucomannan has important satiety property due to volume increase following gelification. The aim of the study is the evaluation of subjective rate of hunger and enterohormone concentrations (CCK, GLP-1, PYY 1–36) following oral loading of a mixture containing WP (8 g) or casein (8 g) plus glucomannan (1 g) (Colordiet®, Inpha DUEMILA Srl Lecco, Italy). The study was conducted as a double-blind crossover with five healthy volunteers (BMI 22–26 kg/m2 aging 18–65 years) in acute and a wash-out period of 1 week between the first and the second evaluation. From the analysis of the data, we observe that the load with WP induces a significant decrease in the desire to eat after 90 min (P < 0.0446) when compared with casein. As far as plasma hormones are concerned, there was a significant increase only in GLP-1 at 90 min after WP (P < 0.00166) and 180 min after casein (T0 vs. T180 P = 0.000129). There is a significant correlation between the increase in GLP-1 and decrease of desire to eat (R = −0.93). There is a tendency to the increasing of CCK after 90 min, which is not significant (P = 0.091). These results could be due to (a) the low number of cases or (b) the low dose of protein used. The present study suggests that a mixture of WP plus glucomannan exerts a decrease in the desire to eat which is correlated to enterohormonal modification (GLP-1 increase) despite the low content of protein (8 g) and the presence of glucomannan, which could reduce the fast absorption of WP in relation to the net forming during the gelification of the gastric environment.
Mediterranean Journal of Nutrition and Metabolism 12/2013; 6(3). DOI:10.1007/s12349-013-0121-7
"Moreover, Berl and Frigyesi (37, 38) previously showed that leucine is metabolized in the small compartment in cat brain. As pointed out by Yudkoff et al. (39, 40), transfer of leucine nitrogen to α-ketoglutarate is favorable in brain, especially in astrocytes. Isoleucine, another BCAA, is of interest because its metabolism will not only replenish glutamate nitrogen in astrocytes, but also generate the TCA cycle intermediates succinyl-CoA and acetyl-CoA (41). "
[Show abstract][Hide abstract] ABSTRACT: In a contribution to this Research Topic Erkki Somersalo and Daniela Calvetti carried out a mathematical analysis of neurotransmitter pathways in brain, modeling compartmental nitrogen flux among several major participants - ammonia, glutamine, glutamate, GABA, and selected amino acids. This analysis is important because cerebral nitrogen metabolism is perturbed in many diseases, including liver disease and inborn errors of the urea cycle. These diseases result in an elevation of blood ammonia, which is neurotoxic. Here, a brief description is provided of the discovery of cerebral metabolic compartmentation of nitrogen metabolism - a key feature of cerebral glutamate-glutamine and GABA-glutamine cycles. The work of Somersalo and Calvetti is discussed as a model for future studies of normal and pathological cerebral ammonia metabolism.
Frontiers in Endocrinology 11/2013; 4:179. DOI:10.3389/fendo.2013.00179
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