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造成的脑损伤是脑瘫和肌张力障碍等运动障碍的主要原因。由于潜在生产力的损失以及个人、家庭和社会机构的负担，从出生开始并持续一生，社会的代价是巨大的。相比之下，CP的疾病负担指数高于许多影响晚年生活的神经退行性疾病。胎儿H-I缺乏可用的治疗方法。随着临床应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，为系统研究胎儿大脑发育到H-I的机制提供了独特的机会。四氢生物蝶呤（BH4）是脑功能正常发育的重要辅助因子。缺乏BH4也与运动障碍的发展有关。我们之前的研究已经确定，在动物模型中观察到的运动缺陷依赖于大脑不同部位的关键BH4缺乏。产前用BH4治疗H-I胎脑可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通过一个双重打击模型来解释，即H-I与发育低BH4的结合。我们假设未成熟大脑中的BH4通路被缺氧缺血损伤选择性地破坏，导致运动缺陷的发展。这一假设将在产前子宫内H-I损伤的胎兔中进行验证。

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.