Stimulation of the brain NO/cyclic GMP pathway by peripheral administration of tetrahydrobiopterin in the hph-1 mouse
Stimulation of the brain NO/cyclic GMP pathway by peripheral administration of tetrahydrobiopterin in the hph-1 mouse
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DOI：
10.1046/j.1471-4159.1999.0732563.x
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发表时间：
1999-12-01
影响因子：
4.7
通讯作者：
Heales, SJR
中科院分区：
文献类型：
--
作者：
Canevari, L;Land, JM;Heales, SJR
GTP-环水解酶 1 (GTP-CH) 突变已被确定会导致一系列先天性代谢错误，包括多巴反应性肌张力障碍。 GTP-CH 催化四氢生物蝶呤 (BH(4)) 生物合成的第一步，四氢生物蝶呤是儿茶酚胺和血清素合成所必需的辅助因子。目前基于单胺神经递质替代的治疗在纠正神经缺陷方面可能仅部分成功。原因可能是 BH(4) 也是一氧化氮合酶的辅助因子。使用突变型 GTP-CH 缺陷 (hph-1) 小鼠品系，我们证明，与野生型动物相比，除了单胺代谢受损之外，BH(4) 缺陷还与大脑中一氧化氮合成减少有关（通过测量环 GMP 水平进行评估）。我们发现所有动物的 BH(4) 水平随着年龄的增长而下降，但没有性别相关的差异。我们发现 hph-1 小鼠中的 BH(4) 和环 GMP 水平之间存在很强的相关性，但在野生型动物中则不然。我们还证明，在 hph-1 小鼠中急性外周注射 BH（100 μmol/kg s.c.）可显着升高脑 BH(4) 浓度以及随后小脑中的环 GMP 水平，分别在 2 小时和 3 小时达到峰值。我们建议，在 BH(4) 缺乏状态下，除了单胺替代疗法外，还应考虑给予 BH(4)。
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 (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, (100 mu mol/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.