Brain amino acid requirements and toxicity: the example of leucine.
ABSTRACT 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.
SourceAvailable from: Peter J M Weijs[Show abstract] [Hide abstract]
ABSTRACT: Proteins and amino acids are widely considered to be subcomponents in nutritional support. However, proteins and amino acids are fundamental to recovery and survival, not only for their ability to preserve active tissue (protein) mass but also for a variety of other functions. Understanding the optimal amount of protein intake during nutritional support is therefore fundamental to appropriate clinical care. Although the body adapts in some ways to starvation, metabolic stress in patients causes increased protein turnover and loss of lean body mass. In this review, we present the growing scientific evidence showing the importance of protein and amino acid provision in nutritional support and their impact on preservation of muscle mass and patient outcomes. Studies identifying optimal dosing for proteins and amino acids are not currently available. We discuss the challenges physicians face in administering the optimal amount of protein and amino acids. We present protein-related nutrition concepts, including adaptation to starvation and stress, anabolic resistance, and potential adverse effects of amino acid provision. We describe the methods for assessment of protein status, and outcomes related to protein nutritional support for critically ill patients. The identification of a protein target for individual critically ill patients is crucial for outcomes, particularly for specific subpopulations, such as obese and older patients. Additional research is urgently needed to address these issues.Critical care (London, England) 11/2014; 18(6):591. DOI:10.1186/s13054-014-0591-0
[Show abstract] [Hide abstract]
ABSTRACT: Autism spectrum disorders are complex developmental disorders with increasing incidence and poorly understood etiology. Imbalance of amino acids profoundly influences brain function, and is thought to be one of the key players in the pathophysiology of autism. This study aimed to measure the plasma amino acid profiles of 20 Egyptian and 20 Saudi autistic patients in comparison to matching healthy controls to clarify the role of impaired amino acid concentrations in the etiology of autism. Plasma amino acids profiles were measured using high performance liquid chromatography. While plasma levels of glutamic, aspartic, and glycine recorded the most significant percentage elevated amino acids, glutamine, asparagine, arginine, tyrosine and isoleucine recorded the most remarkable percentage decrease in autistic patients from both populations compared to controls. Among the calculated relative values, only acidic/basic, and glutamate/glutamine ratios were significantly higher in autistics compared to controls. Non-essential/essential and glucogenic/ketogenic ratios were unaltered in autistics compared to controls. Increased plasma glutamate/glutamine ratio, together with increased glycine, arginine, aspartate, aspargine levels, and acidic/basic amino acid ratio can serve as a predictive tools for the early detection of autism. These findings suggest that glutamatergic abnormalities in the brain may be associated with the pathobiology of autism.Journal of pediatric neurology: JPN 11/2014; 12(4):171-181. DOI:10.3233/JPN-140660
[Show abstract] [Hide abstract]
ABSTRACT: Acute neurological crises involving striatal degeneration induced by a deficiency of glutaryl-CoA dehydrogenase (GCDH) and the accumulation of glutaric (GA) and 3-hydroxyglutaric acid (3-OHGA) are considered to be the most striking features of glutaric aciduria type I (GA1). In the present study, we investigated the mechanisms of apoptosis and energy metabolism impairment in our novel GA1 neuronal model. We also explored the effects of appropriate amounts of amino acids (2 mM arginine, 2 mM homoarginine, 0.45 g/L tyrosine and 10 mM leucine) and 2 g/L glucose on these cells. Our results revealed that the novel GA1 neuronal model effectively simulates the hypermetabolic state of GA1. We found that leucine, tyrosine, arginine, homoarginine or glucose treatment of the GA1 model cells reduced the gene expression of caspase-3, caspase-8, caspase-9, bax, fos, and jun and restored the intracellular NADH and ATP levels. Tyrosine, arginine or homoarginine treatment in particular showed anti-apoptotic effects; increased α-ketoglutarate dehydrogenase complex (OGDC), fumarase (FH), and citrate synthase (CS) expression; and relieved the observed impairment in energy metabolism. To the best of our knowledge, this study is the first to investigate the protective mechanisms of amino acids and glucose in GA1 at the cellular level from the point of view of apoptosis and energy metabolism. Our data support the results of previous studies, indicating that supplementation of arginine and homoarginine as a dietary control strategy can have a therapeutic effect on GA1. All of these findings facilitate the understanding of cell apoptosis and energy metabolism impairment in GA1 and reveal new therapeutic perspectives for this disease.PLoS ONE 10/2014; 9(10):e110181. DOI:10.1371/journal.pone.0110181 · 3.53 Impact Factor