Development of a Neuroprotective Agent For Cerebral Palsy Prevention

描述（由申请人提供）：脑瘫（CP）是儿童时期最常见的身体残疾，在美国有80多万患者，在世界范围内有更多患者。除了运动困难外，许多患有CP的儿童还患有智力障碍、癫痫、营养问题和语言功能障碍。此外，几乎90%的cp相关脑损伤发生在子宫内或出生前后。因此，预防CP的药物需要能够在母亲怀孕期间和/或新生儿出生后不久安全地使用。第一阶段拨款提案的目标是证明一种自然产生的激素可以开发成预防CP的药物的可行性。已经有证据支持这种激素作为抗CP的神经保护剂的作用；这种激素的受体在发育中的大脑中表达，并且这种激素的管理已被证明可以减少神经元细胞死亡，促进发育中的神经元的增殖和体外神经元过程的生长。此外，我们已经确定了流行病学证据表明CP风险与母体平均激素水平呈负相关；在9个不同的流行病学组中，怀孕期间这种激素平均水平较高的妇女的后代患CP的风险较低。在第一阶段，该激素诱导神经保护的能力将在新生小鼠模型中进行研究，该模型产生与CP相似的神经功能缺陷（即遭受长期缺氧缺血性脑损伤的幼鼠）。利用常规的组织化学方法，在缺氧缺血治疗7天后，将激素注射组的新生小鼠与对照组的脑组织损失进行比较。此外，caspase-3激活（新生儿缺氧缺血性损伤时凋亡神经元细胞死亡程度的可量化指标）将在两组之间进行比较。最后，实验组和对照组的神经行为结果将利用已建立的动物行为范式进行检查。在II期，我们将细化hCG给药的浓度、时间和频率，并完成所有临床前hCG安全性实验，为临床试验做准备。

DESCRIPTION (provided by applicant): Cerebral palsy (CP), the most common physical disability in childhood, afflicts more than 800,000 Americans and many more worldwide. In addition to motor difficulties, many children with CP also suffer from intellectual disability, epilepsy, nutritional problems, and language dysfunction. Furthermore, almost 90% of CP-associated brain injuries occur in utero or around the time of birth. Therefore, a medication to prevent CP needs to be able to be safely administered either during pregnancy to the mom and/or shortly after birth to the neonate. The goal of this Phase I grant proposal is to demonstrate the feasibility that a naturally-occurring hormone can be developed into a medicament for CP prevention. There is already evidence supporting the role of this hormone as a neuroprotective agent against CP; receptors for this hormone are expressed in the developing brain, and administration of this hormone has been shown to decrease neuronal cell death, promote the proliferation of developing neurons and the outgrowth of neuronal processes in vitro. Furthermore, we have identified epidemiological evidence of an inverse relationship between CP risk and mean maternal levels of this hormone; offspring from nine epidemiologically distinct groups of women who have higher mean levels of this hormone during pregnancy have a lower CP risk. During Phase I, the capability of this hormone to induce neuroprotection will be investigated in a neonatal mouse model that produces neurological deficits similar to those seen in CP (i.e. pups who have been subjected to term-equivalent hypoxic-ischemic brain injury). Utilizing conventional histochemical methods, the amount of brain tissue loss in a hormone-injected group of neonatal mice will be compared to a control group 7 days after both groups have been subjected to the hypoxia-ischemia regimen. In addition, caspase-3 activation, a quantifiable measure of the extent of apoptotic neuronal cell death in response to neonatal hypoxic-ischemic injury, will be compared between groups. Lastly, the neurobehavioral outcome in the experimental and control groups will be examined utilizing established animal behavioral paradigms. In Phase II, we will refine the concentration, timing and frequency of hCG dosage and perform all preclinical hCG safety experiments to prepare for clinical testing.