MI-773 br Amino acids The role of leucine
Amino acids: The role of leucine Amino MI-773 metabolism plays a central role in brain physiology, as several amino acids serve as biosynthetic precursors for neurotransmitter synthesis . In addition, the amino acids L-leucine and L-lysine may participate in ketogenesis. For these reasons, supplementation with ketogenic amino acids L-leucine or L-lysine was hypothesized to be an interesting alternative to promote ketogenesis while avoiding the harmful side effects of fat-enriched ketogenic diets . One potential risk of using leucine or lysine to counteract epileptic seizures is that free amino acids, particularly leucine, are potent activators of the mTOR (mechanistic Target Of Rapamycin) signaling pathway . Genetic mutations in mTOR regulatory genes that result in mTOR hyperactivation often lead to the onset of seizures. Treatment with mTOR inhibitors, such as rapamycin or other rapalogs, can suppress seizures in genetic models of mTOR hyperactivation . However, the role of mTOR in nongenetic seizure models is not so clear, as rapamycin treatment yielded mixed results, with modest or negligible anticonvulsant effects in some of the models tested , . Interestingly, pre-treatment with L-leucine, but not with L-lysine, conferred resistance to acute seizures in two independent experimental models, the 6Hz test and kainic acid administration . However, L-leucine treatment did not elevate β-hydroxybutyrate levels in blood, suggesting a protective role for L-leucine independent of ketogenesis . Furthermore, the administration of the D-leucine enantiomer conferred even higher protection against acute seizures without evident changes in ketonemia, glycemia, body weight, food or water consumption . Thus, the protective effects of L-leucine and D-leucine seem to be independent from changes in systemic metabolism. Interestingly, D-leucine was capable of attenuating long-term potentiation in the hippocampus. Given that D-leucine cannot be incorporated into proteins, the most feasible explanation is that D-leucine imparts its protective effect by acting on a receptor. However, further experiments failed to identify a potential mechanism mediated by the effect of D-leucine on excitatory or inhibitory receptors . The striking protective effects of D-leucine against acute seizures warrant further investigation to elucidate the underlying mechanisms by which D-leucine modulates neuronal excitability.
Cell-cell metabolic communication So far we have discussed the effects of metabolic pathways on neuronal activity that take place intracellularly. However, metabolism in the brain is defined by a highly complex crosstalk and metabolic exchange between different cellular populations. Such exchange of nutrients is mediated by a series of transporters, such as glucose transporters (GLUTs) and monocarboxylate transporters (MCTs) , . In this context, astrocytes play a prominent role as major metabolic hubs in the brain [reviewed in , . Among other functions, astrocytes uptake nutrients from the bloodstream and supply them to neurons and oligodendrocytes. Astrocytes also contribute to ion homeostasis and participate in biochemical reactions to synthesize, degrade and recycle neurotransmitters . Above we discussed the relevance of lactate in neuronal metabolism and how it contributes to set the pace for neuronal firing rates. Neurons divert a high fraction of their glucose supply to the pentose phosphate shunt. Thus, they need to obtain lactate from exogenous sources . In 1994 it was postulated that astrocytes could supply glycolysis-derived lactate to neurons through the astrocyte-neuron lactate shuttle , . The astrocyte-neuron lactate shuttle model proposed that glutamate released from neuronal depolarization would activate glycolysis in astrocytes, which in turn would produce lactate to supply to neurons as energy fuel. This model fits very well with the aforementioned neuronal need of lactate to cope with an excitotoxic challenge , . One of the main caveats that has been subject of active debate for this model is its physiological relevance in vivo. Alternative, non-excluding models have been proposed. These models suggested that glycolysis can also be increased in neurons upon depolarization, thus releasing lactate that is uptaken by astrocytes . Interestingly, a recent study has provided in vivo evidence of lactate flow from astrocytes to neurons . In this regard, the evidence accumulated over the years underscores that metabolic communication between different cell types in the brain in a region- and physiological context-dependent manner is essential to fine-tune neuronal activity.