title: High dose sapropterin dihydrochloride therapy improves monoamine neurotransmitter turnover in murine phenylketonuria (PKU).
abstract: Central nervous system (CNS) deficiencies of the monoamine neurotransmitters, dopamine and serotonin, have been implicated in the pathophysiology of neuropsychiatric dysfunction in phenylketonuria (PKU). Increased brain phenylalanine concentration likely competitively inhibits the activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), the rate limiting steps in dopamine and serotonin synthesis respectively. Tetrahydrobiopterin (BH4) is a required cofactor for TH and TPH activity. Our hypothesis was that treatment of hyperphenylalaninemic Pah(enu2/enu2) mice, a model of human PKU, with sapropterin dihydrochloride, a synthetic form of BH4, would stimulate TH and TPH activities leading to improved dopamine and serotonin synthesis despite persistently elevated brain phenylalanine. Sapropterin (20, 40, or 100mg/kg body weight in 1% ascorbic acid) was administered daily for 4 days by oral gavage to Pah(enu2/enu2) mice followed by measurement of brain biopterin, phenylalanine, tyrosine, tryptophan and monoamine neurotransmitter content. A significant increase in brain biopterin content was detected only in mice that had received the highest sapropterin dose, 100mg/kg. Blood and brain phenylalanine concentrations were unchanged by sapropterin therapy. Sapropterin therapy also did not alter the absolute amounts of dopamine and serotonin in brain but was associated with increased homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), dopamine and serotonin metabolites respectively, in both wild type and Pah(enu2/enu2) mice. Oral sapropterin therapy likely does not directly affect central nervous system monoamine synthesis in either wild type or hyperphenylalaninemic mice but may stimulate synaptic neurotransmitter release and subsequent metabolism.
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Mailstop L-103, 3181 Sam Jackson Park Rd., Portland, OR 97239, USA.
authors.forename: Shelley R
authors.initials: SR
authors.lastname: Winn
authors.affiliation: Department of Pediatrics, University of Zurich, Steinweissstrasse 75, Zurich CH-8032, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Scherer
authors.affiliation: Department of Pediatrics, University of Zurich, Steinweissstrasse 75, Zurich CH-8032, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Thöny
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Mailstop L-103, 3181 Sam Jackson Park Rd., Portland, OR 97239, USA. Electronic address: hardingc@ohsu.edu.
authors.forename: Cary O
authors.initials: CO
authors.lastname: Harding
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005838:Genotype; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000378:metabolism; D051379:Mice; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010649:Phenylalanine / Q000097:blood; D010661:Phenylketonurias / Q000188:drug therapy* / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D007211:Indoles; D018377:Neurotransmitter Agents; D001708:Biopterins; C026785:5-hydroxyindole; D012701:Serotonin; D010649:Phenylalanine; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase; C003402:sapropterin; D004298:Dopamine; D006719:Homovanillic Acid
keywords: Dopamine; Monoamine neurotransmitters; Phenylketonuria; Sapropterin dihydrochloride; Serotonin; Tetrahydrobiopterin