Striatal Immune Response In Aged Rats

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DESCRIPTION (provided by applicant): The exact mechanisms underlying poor cell survival and graft dysfunction in neural repair paradigms for Parkinson's disease are unknown. However, transplantation-induced oxidative stress and host immune response have been hypothesized as contributing factors as dopamine (DA) neurons are exquisitely sensitive to oxidative damage and inflammation. Therefore, aging-related increases in oxidant stress, decreases in antioxidant protection and production of trophic factors in addition to a suboptimal immune function may provide a more hostile transplant environment, resulting in the decreased efficacy or lack of therapeutic benefit observed in aged individuals receiving transplanted DA neurons. Although multiple studies have attempted to improve overall cell survival by pre-treating the cell transplant material with various anti-apoptotic or antioxidant compounds, these approaches do not address the issue of further decreased cell survival and efficacy in aged recipients. We have recently shown that dietary supplementation with phytochemicals significantly improves the survival of transplanted embryonic DA neurons in both young and old rats. Additionally, functional efficacy of a suboptimal graft was achieved in young animals receiving blueberry extract (BBE). BBE is a fruit extract with immunomodulatory, antioxidant, and anti-inflammatory properties that previously has been shown to restore striatal associated motor function in aged rats. The neurotrophic/immunomodulatory mechanisms that underlie these observations have yet to be explored. The current application proposes to examine the effect of dietary BBE on injury-related aspects of neural transplantation paradigms in young versus old rats. This design allows differentiation of diet induced changes in the mesostriatal system from age-related changes in response to the penetrating wound used to place embryonic cells into the brain. We hypothesize that dietary supplementation with BBE will decrease immune and inflammatory responses and improve trophic factor production in response to a penetrating striatal wound in young and old rats. These studies will provide support for the potential of dietary phytochemicals to provide an efficacious, easily administered and well tolerated therapy that can be used to improve graft survival and function in cell replacement therapies, whether they utilize embryonic tissue or stem cells.