Effects of sex and estrous cycle on the brain and plasma arginine metabolic profile in rats

l -arginine is a versatile amino acid with a number of bioactive metabolites. Increasing evidence implicates altered arginine metabolism in the aging and neurodegenerative processes. The present study, for the first time, determined the effects of sex and estrous cycle on the brain and blood (plasma) arginine metabolic profile in naïve rats. Female rats displayed significantly lower levels of l -arginine in the frontal cortex and three sub-regions of the hippocampus when compared to male rats. Moreover, female rats had significantly higher levels of l -arginine and γ -aminobutyric acid, but lower levels of l -ornithine, agmatine and putrescine, in plasma relative to male rats. The observed sex difference in brain l -arginine appeared to be independent of the enzymes involved in its metabolism, de novo synthesis and blood-to-brain transport (cationic acid transporter 1 protein expression at least), as well as circulating l -arginine. While the estrous cycle did not affect l -arginine and its metabolites in the brain, there were estrous cycle phase-dependent changes in plasma l -arginine. These findings demonstrate the sex difference in brain l -arginine in the estrous cycle-independent manner. Since peripheral blood has been increasingly used to identify biomarkers of brain pathology, the influences of sex and estrous cycle on blood arginine metabolic profile need attention when experimental research involves female rodents.