Entrance of tetrahydropterin derivatives in brain after peripheral administration: effect on biogenic amine metabolism.
The ability of various structural analogs of tetrahydrobiopterin to enter the rat brain and remain in the reduced form after i.p. administration was tested because tetrahydrobiopterin itself enters poorly. The total content of various pterins in different brain areas was measured by high-pressure liquid chromatography-fluorescence detection, whereas high-pressure liquid chromatography-electrochemical detection was used to measure the content of reduced pterins. The effect of injection of certain tetrahydropterins on brain content of biogenic amines and their major metabolites was also monitored. In general, when the position 6 side-chain of tetrahydrobiopterin was made shorter and smaller in size, entrance into the brain from the periphery was markedly enhanced. Increasing the lipophilicity or size of the position 6 side-chain did not allow for better entry into brain and, in some cases, hindered entry. Under the conditions tested, none of the tetrahydropterins influenced the brain content of biogenic amines or their major metabolites; higher brain concentrations of tetrahydropterins are probably necessary to modify central nervous system biogenic amine metabolism. Other types of structural modifications or experimental approaches may be necessary to achieve higher brain concentrations of active cofactors, which may be required for the successful treatment of certain human diseases with tetrahydropterins.
D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D007274:Injections, Intraperitoneal; D008297:Male; D008722:Methods; D011622:Pterins / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D001679:Biogenic Amines; D011622:Pterins; C011552:tetrahydropterin