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Stimulation of the Brain NO/Cyclic GMP Pathway by Peripheral Administration of Tetrahydrobiopterin in the hph‐1 Mouse
Author(s) -
Canevari Laura,
Land John M.,
Clark John B.,
Heales Simon J. R.
Publication year - 1999
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.1471-4159.1999.0732563.x
Subject(s) - tetrahydrobiopterin , monoamine neurotransmitter , gtp cyclohydrolase i , medicine , endocrinology , biopterin , gtp' , nitric oxide , stimulation , chemistry , neurotransmitter , serotonin , nitric oxide synthase , biology , biochemistry , central nervous system , receptor , enzyme
: Mutations in GTP‐cyclohydrolase I (GTP‐CH) have been identified as causing a range of inborn errors of metabolism, including dopa‐responsive dystonia. GTP‐CH catalyses the first step in the biosynthesis of tetrahydrobiopterin (BH 4 ), a cofactor necessary for the synthesis of catecholamines and serotonin. Current therapy based on monoamine neurotransmitter replacement may be only partially successful in correcting the neurological deficits. The reason might be that BH 4 is also a cofactor for nitric oxide synthase. Using a strain of mutant GTP‐CH‐deficient ( hph‐1 ) mice, we demonstrate that in addition to impaired monoamine metabolism, BH 4 deficiency is also associated with diminished nitric oxide synthesis in the brain (as evaluated by measuring the levels of cyclic GMP), when compared with wild‐type animals. We have found a decline in the levels of BH 4 with age in all animals, but no gender‐related differences. We found a strong association between the levels of BH 4 and cyclic GMP in hph‐1 mice but not in wild‐type animals. We also demonstrate that acute peripheral administration of BH 4 (100 μmol/kg s.c.) in hph‐1 mice significantly elevated the brain BH 4 concentration and subsequently cyclic GMP levels in cerebellum, with peaks at 2 and 3 h, respectively. We suggest that BH 4 administration should be considered in BH 4 deficiency states in addition to monoamine replacement therapy.