Stimulation of the brain NO/cyclic GMP pathway by peripheral administration of tetrahydrobiopterin in the hph-1 mouse

Mutations in GTP-cyclohydrolase 1 (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 (BH4), a cofactor necessary for the synthesis of catecholamines and seroto nin. Current therapy based on monoamine neurotransmitter replacement may be only partially successful in correcting the neurological deficits. The rea son might be that BH4 is also a cofactor for nitric oxide synthase. Using a strain of mutant GTP-CH-deficient (hph-1) mice, we demonstrate that in add ition to impaired monoamine metabolism, BH4 deficiency is also associated w ith diminished nitric oxide synthesis in the brain (as evaluated by measuri ng the levels of cyclic GMP), when compared with wild-type animals. We have found a decline in the levels of BH4 with age in all animals, but no gende r-related differences. We found a strong association between the levels of BH4 and cyclic GMP in hph-1 mice but not in wild-type animals. We also demo nstrate that acute peripheral administration of BH, (100 mu mol/kg s.c.) in hph-1 mice significantly elevated the brain BH4 concentration and subseque ntly cyclic GMP levels in cerebellum, with peaks at 2 and 3 h, respectively . We suggest that BH4 administration should be considered in BH4 deficiency states in addition to monoamine replacement therapy.