Striatal Immune Response In Aged Rats

描述（由申请人提供）：帕金森病神经修复范式中细胞存活不良和移植物功能障碍的确切机制尚不清楚。然而，由于多巴胺（DA）神经元对氧化损伤和炎症非常敏感，移植诱导的氧化应激和宿主免疫反应被假设为促成因素。因此，衰老相关的氧化应激的增加、抗氧化保护的减少和营养因子的产生，以及次优的免疫功能，可能会提供一个更恶劣的移植环境，导致在接受移植DA神经元的老年人中观察到的疗效下降或缺乏治疗益处。尽管多项研究试图通过用各种抗凋亡或抗氧化化合物预处理细胞移植材料来提高总体细胞存活率，但这些方法并不能解决老年受体进一步降低细胞存活率和疗效的问题。我们最近的研究表明，在幼龄和老年大鼠中，膳食中添加植物化学物质可显著提高移植胚胎DA神经元的存活率。此外，在接受蓝莓提取物（BBE）的幼龄动物中实现了次优移植物的功能功效。BBE是一种具有免疫调节、抗氧化和抗炎特性的水果提取物，先前已被证明可以恢复老年大鼠纹状体相关的运动功能。这些观察结果背后的神经营养/免疫调节机制尚未被探索。目前的应用建议检查饮食BBE对年轻和老年大鼠神经移植范式损伤相关方面的影响。这种设计允许将饮食引起的中纹体系统变化与用于将胚胎细胞植入大脑的穿透性伤口引起的年龄相关变化区分开来。我们假设饮食中补充BBE会降低免疫和炎症反应，并改善年轻和年老大鼠对穿透纹状体伤口的反应中的营养因子产生。这些研究将为膳食植物化学物质的潜力提供支持，提供一种有效、易于施用和耐受性良好的治疗方法，可用于改善移植物存活和细胞替代疗法的功能，无论它们是利用胚胎组织还是干细胞。

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.