Kinetic Behavior of Leucine and Other Amino Acids Modulating Cognitive Performance via mTOR Pathway.

摘要

There are reports in the literature showing one of the essential amino acids (AAs), leucine, playing a role in enhancing cognition and memory in animal and man, partially via the mammalian target of rapamycin (mTOR) signaling pathway regulating neuronal protein synthesis and plasticity. This pathway is a potential target for modulation with leucine (or other therapeutic agents), to maintain/enhance normal functioning under stress conditions. Such an effect has potential for optimizing warfighter cognitive performance under high demand conditions. The kinetic behavior of leucine is, however, not well characterized. Most published studies involve uptake of leucine-enhanced drinking water or diet, and concentrations of leucine in tissues are typically measured at only one time point at the study's end (Tews and Harper 1991). To fill these data gaps and to develop a physiologically-based pharmacokinetic (PBPK) leucine model, an iv leucine study was performed in Long-Evans rats, collecting both time-course and dose-response blood and tissue data. Such a PBPK model, once validated, will allow extrapolation of leucine dosing and intake across dosing regimens (drinking water, diet) and across species to predict potential brain concentration changes in man. Brain concentrations in both animals and man can then be linked with potential impacts on the mTOR signaling pathway, and on observed cognitive changes. Preliminary results revealed that leucine is eliminated from the blood very quickly after iv dosing (5mg/kg), and leucine levels in the brain were higher than blood, indicating active transport of leucine across the blood-brain-barrier (BBB). At 5 min post dosing, only 7% of injected leucine was detected still in blood, and at 6 hr post doing it was down to base line levels. Similarly, of the 17 other AAs measured in brain, about 2/3 were increased, even at very early times.