Neuroinflammatory Mechanisms in FASD: Development of Novel Therapeutic Strategies

描述（由申请人提供）：尽管公共卫生部门竭尽全力阻止孕妇在怀孕期间饮酒，但仍有12%的孕妇饮酒，胎儿酒精谱系障碍（FASD）的发病率在美国估计为1/100，FASD没有有效的治疗方法，其神经系统后遗症持续一生。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。利用人类妊娠晚期胎儿酒精暴露的新生小鼠模型，我们发现在发育中的大脑中，不仅神经元而且小胶质细胞都是乙醇的靶标。具体来说，乙醇会导致神经元和小胶质细胞的丧失，并激活存活的小胶质细胞。小胶质细胞的激活是诱导神经炎症的关键。在这种情况下，我们的

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.