Neuroinflammatory Mechanisms in FASD: Development of Novel Therapeutic Strategies

描述（由申请人提供）：尽管在公共卫生方面做出了详尽的努力来阻止孕妇在怀孕期间饮酒，但仍有12%的孕妇饮酒，并且在美国，胎儿酒精谱系障碍（FASD）的发病率估计为1/100。小脑损伤在FASD中很常见，导致运动协调、平衡和步态缺陷。动物模型已经开始揭示FASD的潜在机制。使用人类妊娠晚期胎儿酒精暴露的新生小鼠模型，我们发现，不仅神经元，而且小胶质细胞是乙醇在发育中的大脑中的目标。具体来说，乙醇会导致神经元和小胶质细胞的损失，并激活存活的小胶质细胞。小胶质细胞活化是诱导神经炎症的关键。在这方面，我们 初步数据显示乙醇诱导神经炎性细胞因子和趋化因子的表达。有趣的是，我们发现抗炎的过氧化物酶体增殖体激活受体β激动剂吡格列酮阻断乙醇诱导的神经元和小胶质细胞的损失、小胶质细胞的激活和神经炎性分子的表达。这些发现使我们假设，乙醇诱导的炎症在发育中的大脑有助于与FASD相关的神经病理学和行为缺陷。我们进一步假设，在乙醇暴露期间或之后用抗炎剂治疗将改善乙醇诱导的行为缺陷。最后，我们假设乙醇诱导的神经炎症将在停止乙醇暴露后持续存在，导致FASD中使用抗炎药物的治疗窗口延长。目的1将确定是否可以通过在乙醇暴露期间使用抗炎性PPAR-β激动剂吡格列酮来预防长期乙醇诱导的行为运动功能缺陷。目的2将（A）研究乙醇暴露后神经炎症活动的时间过程，以确定治疗干预的延长窗口，（B）确定乙醇暴露后在延长的治疗窗口中使用抗炎性PPAR-β激动剂吡格列酮治疗是否可以预防长期行为运动功能缺陷。意义：第一次，抗炎药物将被检查对FASD行为缺陷的保护作用。拟议的研究将定义神经炎症相关FASD神经病理学和行为缺陷治疗干预的时间窗。因此，拟议的研究将促进开发用于干预FASD的强大的新抗炎策略。

DESCRIPTION (provided by applicant): Despite exhaustive public health efforts to stem maternal drinking during pregnancy, a staggering 12% of pregnant women still drink alcohol and the incidence This of fetal alcohol spectrum disorders (FASD) is estimated at 1/100 births in the U.S. There is no effective treatment for FASD and the neurological sequelae persist throughout life. Damage to the cerebellum is common in FASD, leading to deficits in motor coordination, balance and gait. Animal models have begun to unravel the mechanisms underlying FASD. Using the neonatal mouse model of human third trimester fetal alcohol exposure, we have discovered that not only neurons but also microglia are targets of ethanol in the developing brain. Specifically, ethanol causes loss of neurons and microglia, and activates the surviving microglia. Microglial activation is pivotal to induction of neuroinflammation. In this context, our preliminary data reveal that expression of neuroinflammatory cytokines and chemokines is induced by ethanol. Interestingly, we discovered that the anti-inflammatory PPAR-� agonist pioglitazone blocks ethanol-induced loss of neurons and microglia, microglial activation, and expression of neuroinflammatory molecules. These findings led us to hypothesize that ethanol-induced inflammation in the developing brain contributes to the neuropathology and behavioral deficits associated with FASD. We further hypothesize that treatment with anti-inflammatory agents during or after ethanol exposure will ameliorate ethanol-induced behavioral deficits. Finally, we hypothesize that ethanol-induced neuroinflammation will persist following cessation of ethanol exposure, resulting in a protracted therapeutic window for use of anti- inflammatory pharmaceuticals in FASD. Aim 1 will determine whether long-term ethanol-induced behavioral motor function deficits can be prevented by treatment with the anti-inflammatory PPAR-� agonist pioglitazone during the period of ethanol exposure. Aim 2 will (A) investigate neuroinflammatory activity in a time-course after ethanol exposure to define extended windows for therapeutic intervention and (B) determine whether treatment with the anti-inflammatory PPAR-� agonist pioglitazone in an extended therapeutic window after ethanol exposure will prevent long-term behavioral motor function deficits. Significance: For the first time, an anti-inflammatory pharmaceutical will be examined for protective effects against FASD behavioral deficits. The proposed studies will define temporal windows for therapeutic intervention in neuroinflammation-linked FASD neuropathology and behavioral deficits. Thus, the proposed studies will foster development of powerful new anti-inflammatory strategies for intervention in FASD.