Alcohol abuse during pregnancy can profoundly affect the fetus, resulting in fetal alcohol syndrome (FAS). A leading cause of mental retardation, FAS is a major public health problem. In the developing brain, neuronal death is one of alcohol's most prominent pathologic effects. Thus, identification of agents that can prevent alcohol-induced neuronal death is a high priority. We have demonstrated that stimulation of a particular signaling pathway, the cAMP-PKA-CREB pathway, protects immature neurons against alcohol toxicity. Because elevated intracellular cAMP concentrations activate this pathway, agents that increase cAMP levels may protect neurons against alcohol toxicity. Phosphodiesterases control the intracellular concentration of cAMP by degrading it. Within neurons, cAMP is degraded by phosphodiesterase 4 (PDE4). Inhibition of PDE4 leads to the accumulation of cAMP and activation of the cAMP-PKA-CREB pathway in neurons. Thus, an inhibitor of PDE4 could protect neurons by activating the cAMP-PKA- CREB pathway. Rolipram is a specific inhibitor of PDE4. In rodent neurons, rolipram increases intracellular cAMP concentrations and activates CREB. Thus, we hypothesize that rolipram can protect developing neurons against alcohol toxicity by increasing intracellular cAMP levels to stimulate the cAMP-PKA-CREB pathway. The cAMP-PKA- CREB pathway exerts its protective actions via the transcription factor CREB, which alters gene expression to promote cellular survival. Neuronal nitric oxide synthase (nNOS) protects developing neurons against alcohol-induced death and is a downstream target of the cAMP-PKA-CREB pathway. Thus, we hypothesize that Rolipram and the cAMP-PKA-CREB pathway utilize nNOS to produce their neuroprotective effects against alcohol toxicity. In this proposal, we will determine whether rolipram increases cAMP levels and activates CREB, both in cultured neurons and in vivo. We will determine whether pretreatment with rolipram can ameliorate alcohol-induced death of cultured neurons and of neurons within the brains of developing mice. We will examine whether rolipram increases the expression of nNOS in cerebellar granule cells and Purkinje cells. We will determine the importance of nNOS for rolipram's protective effects, by examining rolipram's survival-promoting actions in wild type and nNOS-/- neurons. Thus, these studies will examine the efficacy and mechanism of rolipram as a neuroprotective agent against alcohol neuroteratogenicity.
Alcohol abuse during pregnancy can profoundly affect the fetus and cause fetal alcohol syndrome (FAS), which is a leading cause of mental retardation and a major public health problem. We have discovered that a particular intracellular signaling pathway, referred to as the cAMP pathway, can protect cultured neurons in the laboratory against alcohol toxicity. In this study we propose to treat mice with rolipram, an antidepressant drug used in Europe and Japan, to stimulate the cAMP pathway to protect their brain cells against alcohol toxicity.
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