Striatal Immune Response In Aged Rats

描述(由申请人提供)：帕金森氏病神经修复范例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认为是促成因素。因此，随着年龄的增长，氧化应激增加，抗氧化保护减少，营养因子的产生减少，再加上免疫功能不佳，可能会提供一个更不利的移植环境，导致接受DA神经元移植的老年人的疗效降低或缺乏治疗益处。尽管多项研究试图通过用各种抗凋亡或抗氧化化合物对细胞移植材料进行预处理来提高整体细胞存活率，但这些方法并没有解决老年受者细胞存活率和有效性进一步下降的问题。我们最近发现，饮食中添加植物化学物质显著提高了幼年和老年大鼠移植的胚胎DA神经元的存活率。此外，在接受蓝莓提取物(BBE)的幼年动物中，次优移植物的功能效果也得到了实现。BBE是一种具有免疫调节、抗氧化和抗炎特性的水果提取物，以前已被证明可以恢复老年大鼠的纹状体相关运动功能。这些观察结果背后的神经营养/免疫调节机制还有待探索。目前的应用建议检查饮食BBE对幼年和老年大鼠神经移植范例中与损伤相关的方面的影响。这种设计允许区分饮食诱导的中纹状体系统变化与年龄相关的变化，以响应用于将胚胎细胞放置到大脑中的穿透伤。我们假设饮食中补充BBE会降低免疫和炎症反应，并提高营养因子的产生，以应对幼年和老年大鼠的纹状体穿透伤。这些研究将支持膳食植物化学物质提供一种有效、易于管理和耐受性良好的疗法的潜力，这种疗法可用于提高细胞替代疗法中移植物的存活率和功能，无论这些疗法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.