High dose sapropterin dihydrochloride therapy improves monoamine neurotransmitter turnover in murine phenylketonuria (PKU)

详细信息    查看全文

• 作者：Shelley R. Winn^a ; Tanja Scherer^b ; Beat Thö ; ny^b ; Cary O. Harding^a ; ^{hardingc@ohsu.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：BH4 ; tetrahydrobiopterin ; TH ; tyrosine hydroxylase ; TPH ; tryptophan hydroxylase ; HVA ; homovanillic acid ; 5-HIAA ; 5-hydroxyindoleacetic acid
• 刊名：Molecular Genetics and Metabolism
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：117
• 期：1
• 页码：5-11
• 全文大小：765 K

文摘

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 100 mg/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, 100 mg/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.