520S troke is a leading cause of death and long-term disabilities worldwide. Despite years of intense research and preclinical identification of numerous potential neuroprotective compounds, the only available treatment for brain ischemia relies on thrombolysis through injection of a recombinant tissuetype plasminogen activator. However, the treatment benefits to <10% of stroke victims because of a narrow therapeutical time window (<4.5 hours after stroke onset) and side effects. Consequently, there is a crucial need for the development of other strategies that could target later phases of the pathophysiological cascade of events after stroke.Since its initial discovery, several studies have highlighted the neuroprotective effect of pituitary adenylate cyclase-activating polypeptide (PACAP) 2 in in vitro and in vivo models of neurodegenerative diseases.3,4 Administered either before or few hours after middle cerebral artery occlusion, PACAP reduces the infarct volume area and improves functional outcomes. [5][6][7] Beside its well-known antiapoptotic activity, the neuropeptide PACAP exerts potent anti-inflammatory properties on innate immune compartment as illustrated by the decrease of the production of proinflammatory mediators interleukin (IL)-12, tumor necrosis factor (TNF)-α, and nitric oxide and the induction of the anti-inflammatory cytokine IL-10 in PACAP-treated macrophages stimulated by lipopolysaccharides.8-10 Whether PACAP acts directly by reducing apoptotic neuronal death 11 or indirectly via modulation of Background and Purpose-Until now, except thrombolysis, the therapeutical strategies targeting the acute phase of cerebral ischemia have been proven ineffective, and no approach is available to attenuate the delayed cell death mechanisms and the resulting functional deficits in the late phase. Then, we investigated whether a targeted and delayed delivery of pituitary adenylate cyclase-activating polypeptide (PACAP), a peptide known to exert neuroprotective activities, may dampen delayed pathophysiological processes improving functional recovery. Methods-Three days after permanent focal ischemia, PACAP-producing stem cells were transplanted intracerebroventricularly in nonimmunosuppressed mice. At 7 and 14 days post ischemia, the effects of this stem cell-based targeted delivery of PACAP on functional recovery, volume lesions, and inflammatory processes were analyzed. Results-The
A major cause of alcohol toxicity is the production of reactive oxygen species generated during ethanol metabolism. The aim of this study was to compare the effect of binge drinkinglike alcohol exposure on a panel of genes implicated in oxidative mechanisms in adolescent and adult mice. In adolescent animals, alcohol decreased the expression of genes involved in the repair and protection of oxidative DNA damage such as atr, gpx7, or nudt15 and increased the expression of proapoptotic genes such as casp3. In contrast, in the adult brain, genes activated by alcohol were mainly associated with protective mechanisms that prevent cells from oxidative damage. Whatever the age, iterative binge-like episodes provoked the same deleterious effects as those observed after a single binge episode. In adolescent mice, multiple binge ethanol exposure substantially reduced neurogenesis in the dentate gyrus and impaired short-term memory in the novel object and passive avoidance tests. Taken together, our results indicate that alcohol causes deleterious effects in the adolescent brain which are distinct from those observed in adults. These data contribute to explain the greater sensitivity of the adolescent brain to alcohol toxicity.
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