NEUROCHEMICAL EFFECTS FOLLOWING PERIPHERAL ADMINISTRATION OF TETRAHYDROPTERIN DERIVATIVES TO THE HPH-1 MOUSE

The hph-1 mouse, which displays tetrahydrobiopterin deficiency and imp aired dopamine and serotonin turnover, has been used to study cofactor replacement therapy for disorders causing brain tetrahydrobiopterin d eficiency. Subcutaneous administration of 100 mu mol/kg (30 mg/kg) of tetrahydrobiopterin resulted in a twofold increase in brain cofactor c oncentration 1 h after administration. Concentrations remained above t he endogenous level for at least 4 h but returned to normal by 24 h. T he lipophilic tetrahydrobiopterin analogue 6-methyltetrahydropterin en tered the brain five times more efficiently than tetrahydrobiopterin b ut was cleared at a faster rate. Tetrahydropterins linked to the lipoi dal carrier N-benzyl-1,4-dihydronicotinoyl did not result in a detecta ble increase in levels of brain pterins over the period of the study ( 1-4 h). Stimulation of monoamine turnover was not observed at any time point with either natural cofactor or the methyl analogue. Increasing the amount of tetrahydrobiopterin to 1,000 mu mol/kg resulted in elev ation of cofactor concentrations, a brief increase in the activity of tyrosine and tryptophan hydroxylase 1 h postadministration, and increa sed turnover of dopamine and serotonin metabolites lasting 24 h. Howev er, 2 of 12 (17%) mice died following administration of this dose of c ofactor. Our findings suggest that acute peripheral tetrahydrobiopteri n administration is unlikely to stimulate brain monoamine turnover dir ectly unless very large and potentially toxic doses of cofactor are us ed.