Sapropterin dihydrochloride (6R-BH4 dihydrochloride), a synthetic formulation of the active 6R isoform of tetrahydrobiopterin, is effective in reducing blood phenylalanine levels[1]. Sapropterin dihydrochloride has been widely used in the treatment of hyperphenylalaninemia[2].
In vitro, Sapropterin dihydrochloride treatment (100μM; 24h) prevented estrogen-stimulated oxidant generation and superoxide production in diabetic patient-derived coronary endothelial cells[3].
In vivo, Sapropterin dihydrochloride treatment (10 mg/kg/day; p.o.) for 20 days in diabetic adult female C57BL/6 mice can increase eNOS activity and reduce oxidative stress in fetal heart, and reduce coronary artery malformations in offspring with pregestational diabetes[4]. In mice with autoimmune encephalomyelitis (EAE), treatment with Sapropterin dihydrochloride for 20 days (2mg/kg/day; p.o), which aggravated EAE in mice, accompanied by increased plasma levels of medium and long-chain ceramides and decreased levels of polyunsaturated fatty acid linolenic acid (FA18:3)[5]. Oral administration of Sapropterin dihydrochloride at the dose of 20mg/kg/day for one week improved pulmonary hypertension induced by chronic hypoxia in newborn pigs[6]. Oral administration of Sapropterin dihydrochloride (100mg/kg/day) for 4 days improved monoamine neurotransmitter turnover and stimulated synaptic neurotransmitter release and subsequent metabolism in mice with phenylketonuria[7].
References:
[1] Sanford M, Keating G M. Sapropterin: a review of its use in the treatment of primary hyperphenylalaninaemia[J]. Drugs, 2009, 69: 461-476.
[2] Lachmann R. Sapropterin hydrochloride: Enzyme enhancement therapy for phenylketonuria[J]. Therapeutic Advances in Endocrinology and Metabolism, 2011, 2(3): 127-133.
[3] Winkler J, Ma H, Zhu S, et al. Estrogen-induced Superoxide Production in Coronary Artery Endothelial Cells via Uncoupled Nitric Oxide Synthase in Diabetes[J]. The FASEB Journal, 2016, 30: 716.3-716.3.
[4] Engineer A, Lim Y J, Lu X, et al. Sapropterin reduces coronary artery malformation in offspring of pregestational diabetes mice[J]. Nitric Oxide, 2020, 94: 9-18.
[5] Schmitz K, Trautmann S, Hahnefeld L, et al. Sapropterin (BH4) aggravates autoimmune encephalomyelitis in mice[J]. Neurotherapeutics, 2021, 18(3): 1862-1879.
[6] Dikalova A, Aschner J L, Kaplowitz M R, et al. Tetrahydrobiopterin oral therapy recouples eNOS and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs[J]. American Journal of Physiology-Lung Cellular and Molecular Physiology, 2016, 311(4): L743-L753.
[7] Winn S R, Scherer T, Thöny B, et al. High dose sapropterin dihydrochloride therapy improves monoamine neurotransmitter turnover in murine phenylketonuria (PKU)[J]. Molecular genetics and metabolism, 2016, 117(1): 5-11.
Sapropterin dihydrochloride (6R-BH4 dihydrochloride)是四氢生物蝶呤活性6R异构体的合成制剂，可有效降低血液苯丙氨酸水平[1]。Sapropterin dihydrochloride已广泛应用于高苯丙氨酸血症的治疗[2]。
在体外，100μM浓度的Sapropterin dihydrochloride处理24小时，能抑制糖尿病患者来源的冠状动脉内皮细胞中由雌激素刺激的活性氧生成及超氧化物产生[3]。
在体内，Sapropterin dihydrochloride处理（10mg/kg/day；p.o.）妊娠期糖尿病成年雌性C57BL/6小鼠20天后，可提升胎儿心脏eNOS活性、减轻氧化应激，并降低子代冠状动脉畸形发生率[4]。Sapropterin dihydrochloride处理（2mg/kg/day；p.o.）20天后导致自身免疫性脑脊髓炎（EAE）小鼠病情加重，伴随血浆中长链神经酰胺水平升高及多不饱和脂肪酸亚麻酸（FA18:3）水平降低[5]。Sapropterin dihydrochloride经口服给药（20mg/kg/day）处理一周后可改善新生小猪中由慢性缺氧诱导的肺动脉高压[6]。Sapropterin dihydrochloride经口服给药（20mg/kg/day）处理4天后导致苯丙酮尿症小鼠中单胺类神经递质代谢改善，突触神经递质释放及后续代谢活动增强[7]。