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Neurochemical Effects Following Peripheral Administration of Tetrahydropterin Derivatives to the hph‐1 Mouse
Author(s) -
Brand Michael P.,
Hyland Keith,
Engle Todd,
Smith Isabel,
Heales Simon J. R.
Publication year - 1996
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1996.66031150.x
Subject(s) - tetrahydrobiopterin , neurochemical , cofactor , monoamine neurotransmitter , medicine , chemistry , endocrinology , dopamine , biopterin , tyrosine , tyrosine hydroxylase , serotonin , pharmacology , biochemistry , enzyme , receptor
The hph‐1 mouse, which displays tetrahydrobiopterin deficiency and impaired dopamine and serotonin turnover, has been used to study cofactor replacement therapy for disorders causing brain tetrahydrobiopterin deficiency. Subcutaneous administration of 100 µmol/kg (30 mg/kg) of tetrahydrobiopterin resulted in a twofold increase in brain cofactor concentration 1 h after administration. Concentrations remained above the endogenous level for at least 4 h but returned to normal by 24 h. The lipophilic tetrahydrobiopterin analogue 6‐methyltetrahydropterin entered the brain five times more efficiently than tetrahydrobiopterin but was cleared at a faster rate. Tetrahydropterins linked to the lipoidal carrier N ‐benzyl‐1,4‐dihydronicotinoyl did not result in a detectable 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 µmol/kg resulted in elevation of cofactor concentrations, a brief increase in the activity of tyrosine and tryptophan hydroxylase 1 h postadministration, and increased turnover of dopamine and serotonin metabolites lasting 24 h. However, 2 of 12 (17%) mice died following administration of this dose of cofactor. Our findings suggest that acute peripheral tetrahydrobiopterin administration is unlikely to stimulate brain monoamine turnover directly unless very large and potentially toxic doses of cofactor are used.