Tetrahydrobiopterin in Fetal Hypoxic Brain Injury

描述(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造成的脑损伤是运动损伤的主要原因，如脑瘫和肌张力障碍。社会的代价是巨大的，因为失去了潜在的生产力，并给个人、家庭和社会机构带来了负担，从出生就开始并持续整个一生。与许多影响中年的神经退行性疾病相比，CP具有更高的疾病负担指数。可用于治疗胎儿H-I的治疗方法很少。随着临床上普遍适用的脑性瘫痪动物模型的出现、研究自由基损伤的创新方法以及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对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。BH4缺乏也与运动障碍的发展有关。我们之前的研究已经证实，在动物模型中观察到的运动缺陷取决于大脑不同部位的临界BH4缺乏。在出生前用BH4治疗胎儿大脑，可显著减少出生后观察到的运动缺陷。因此，我们提出，运动障碍的发展可以用双击式模型来解释，即H-I和发育水平较低的BH4。我们假设，未成熟脑中的BH4通路被缺氧缺血损伤选择性地扰乱，导致运动障碍的发展。这一假设将在胎兔出生前遭受宫内H-I损伤的情况下得到验证。 利用这个模型，我们将(1)阐明BH4浓度是否存在导致严重胎儿脑损伤的阈值；(2)研究神经元中BH4的局部生物合成缺陷是否决定了H-I后运动障碍的发展；(3)阐明BH4治疗是否通过涉及氧化还原的机制起作用。BH4对大脑反应的影响将通过使用最先进的分析方法来评估，以表征BH4和BH4合成途径在未成熟大脑中的变化。此外，磁共振成像分析将有助于识别神经行为缺陷的高危胎儿。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，并扩大BH4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.