Modulation of the carrier-mediated transport of the Tyr-MIF-1 across the blood-brain barrier by essential amino acids.

There is evidence that the carrier-mediated system capable of transporting small, N-tyrosinated peptides [e.g., Tyr-Pro-Leu-Gly-NH2 (N-Tyr-MIF-1) and enkephalins] across the blood-brain barrier is modulated by intraventricularly administered leucine. This raises the possibility that the toxicity of amino acids on the central nervous system may be mediated in part by alterations in blood-brain barrier function. We further examined this action of leucine and extended the investigation to include other essential amino acids. High doses of leucine (30 nM and 100 nM/mouse intraventricularly) were found to inhibit significantly transport of iodinated Tyr-MIF-1 out of the brain. Less consistently, a low dose of leucine (1.0 nM/mouse) stimulated transport. Kinetic analysis indicated that leucine produced an uncompetitive type of modulation, probably interacting with the carrier-ligand complex. Among the other amino acids studied, D-leucine inhibited transport at both 1 nM and 100 nM/mouse, but stimulated transport at 0.1 nM/mouse. The only other significant changes occurred at the high (100 nM) dose of arginine, which stimulated, and methionine, which inhibited, transport. The possibility is proposed that derangements in amino acid metabolism might produce some of their effects on the central nervous system by modulating the blood-brain barrier transport systems for peptides and possibly other substances.