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Neuroinflammatory Mechanisms in FASD: Development of Novel Therapeutic Strategies

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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.

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