Age-related changes in arginine and its metabolites in memory-associated brain structures.

L-arginine is metabolised by nitric oxide synthase (NOS) and arginase to form L-citrulline and nitric oxide, and L-ornithine and urea, respectively. The present study investigated NOS and arginase activities, and the levels of L-arginine, L-citrulline and L-ornithine, as well as glutamate and gamma-aminobutyric acid (GABA), in memory-related brain structures in 4, 12 and 24 months old rats. Significantly increased NOS and arginase activities with age were found across the CA1, CA2/3 and dentate gyrus (DG) sub-regions of the hippocampus and the prefrontal, entorhinal, perirhinal, postrhinal and temporal cortices in a region-specific manner. For L-arginine, there were age-related increases in CA1 and the perirhinal and temporal cortices, and decreases in the entorhinal and postrhinal cortices. L-citrulline levels were decreased with age in the prefrontal, postrhinal and temporal cortices. There were age-related decreases in L-citrulline/L-arginine molar ratio in CA1 and CA2/3 and the prefrontal and temporal cortices, but an increase in the entorhinal cortex (EC). Increased L-ornithine levels and L-ornithine/L-arginine molar ratios with age were found in most of the brain regions examined. Glutamate levels were significantly decreased with age in the prefrontal, entorhinal, perirhinal and temporal cortices, whereas GABA level was largely unchanged except for age-related increase in CA1. There were significantly decreased glutamate/GABA molar ratios with age in six brain regions. Correlational analyses revealed no inverse relationship between NOS and arginase activities, and no positive correlations between the activities of the two enzymes and the tissue concentrations of their products. Interestingly, there were significant positive correlations between glutamate and GABA, and L-arginine and its metabolites in many brain regions. These results demonstrate that the aging process has dramatic effects on the NOS and arginase metabolic pathways of L-arginine and the glutamatergic neurotransmitter system. Since L-arginine metabolism is complex, there is a need to determine its metabolomic profile in vivo in the future.