Tetrahydrobiopterin in Fetal Hypoxic Brain Injury

描述（由申请人提供）：围产期缺氧缺血（H-I）脑损伤是儿童获得性残疾的重要危险因素。H-I引起的脑损伤是运动障碍的主要原因，例如在脑瘫和肌张力障碍中发现的运动障碍。社会的代价是巨大的，因为潜在生产力的损失以及个人、家庭和社会机构的负担，从出生开始，持续一生。相比之下，CP的疾病负担指数高于许多影响老年人的神经退行性疾病。胎儿H-I的治疗方法很少。随着临床适用的脑瘫动物模型的可用性，研究自由基损伤的创新方法和新的非侵入性损伤标志物的整合，出现了系统地研究发育中的胎儿脑对H-I的机制的独特机会。四氢生物蝶呤（BH 4）是脑功能正常发育的重要辅助因子。BH 4的缺乏也与运动残疾的发展有关。我们以前的研究已经确定，在动物模型中观察到的运动缺陷取决于大脑不同部位的关键BH 4缺乏。出生前在H-I之前用BH 4处理胎儿脑显著降低出生后观察到的运动缺陷。因此，我们提出，运动缺陷的发展可以解释一个双重打击模型，H-I与发展低BH 4相结合。我们推测，在未成熟的大脑中，BH 4通路被缺氧缺血损伤选择性地破坏，导致运动缺陷的发展。将在产前子宫内H-I损伤的胎兔中检验这一假设。 使用该模型，我们将（1）阐明是否存在引起严重胎儿脑损伤的BH 4浓度阈值;（2）研究神经元中BH 4的局部生物合成缺陷是否决定H-I后运动缺陷的发展;（3）阐明BH 4处理是否通过涉及氧化还原的机制起作用。将通过使用最先进的分析方法来表征BH 4和BH 4合成途径在未成熟大脑中的变化来评估BH 4在大脑反应中的影响。此外，磁共振成像分析将有助于识别神经行为缺陷的风险胎儿。这项工作的成功完成将有望弥合胎儿脑损伤机制之间的知识差距差距，并拓宽BH 4疗法在预防和改善儿童运动障碍方面的潜在应用。

DESCRIPTION (provided by applicant): Perinatal hypoxia ischemia (H-I) brain damage is an important risk factor for acquired disabilities in children. Brain damage from H-I is a main cause of motor impairments such as those found in cerebral palsy and dystonia. The costs to society are huge, because of loss of potential productivity and the burden on the individual, family and social institutions, starting at birth and lasting an entire lifetime. Comparatively, CP has a highr index of burden of disease than many neurodegenerative diseases affecting the twilight years of life. There is a paucity of therapies available for fetal H-I. With the availability of a clinicall applicable animal model of cerebral palsy, innovative methods of investigating free radical damage and the integration of new non- invasive markers of injury a unique opportunity arises to systematically investigate the mechanisms of the developing fetal brain to H-I. Tetrahydrobiopterin (BH4) is an important cofactor in normal development of brain function. Deficiency of BH4 is also associated with development of motor disabilities. Our previous research has identified that motor deficits observed in the animal model is dependent on critical BH4 deficiency in different parts of the brain. Treatment of fetal brain with BH4 prior to H-I before birth significantly decreases motor deficits observed after birth. Thus we propose that development of motor deficits can be explained by a double-hit model, H-I in combination with developmentally low BH4. We hypothesize that the BH4 pathway in immature brain is selectively disrupted by hypoxia-ischemia injury leading to development of motor deficits. This hypothesis will be tested in fetal rabbits subjected to in utero H-I injury in the prenatal period. Using this model we will (1) elucidate if there is a threshold for BH4 concentration causing critical fetal brain injury; (2) investigate if the regional biosynthetic deficits of BH4 in neuron determines the development of motor deficits after H-I; (3) elucidate if BH4 treatment acts through a mechanism that involves oxidation- reduction. The influence of BH4 in the brain responses will be assessed by using state-of-the-art analytical methodologies to characterize BH4, and BH4 synthetic pathway changes in the immature brain. Additionally magnetic resonance imaging analysis will help in the identification of at-risk fetuses for neurobehavioral deficits. The successful completion of this work will hopefully bridge the gap in knowledge between the mechanisms of fetal brain injury and in broadening the potential application of BH4 therapies in the prevention and improvement of movement disorders in children.