Freeze-Dried Blueberries: Prevention and Rehabilitation Strategies in MS

冻干蓝莓：多发性硬化症的预防和康复策略

• 批准号: 8003795
• 负责人: SUSAN O MCGUIRE
• 金额: --
• 依托单位: EDWARD HINES JR VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003795
• 关键词: Address; Adjuvant; Adverse effects; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Astrocytes; Behavior; Blueberries; Botanicals; Caring; Chronic; Clinical; Cognition; Complementary and alternative medicine; Development; Diet; Diet therapy; Dietary Supplementation; Disease; Dose; Effector Cell; Experimental Autoimmune Encephalomyelitis; Fatigue; Flavonoids; Freeze Drying; Healthcare; Heat-Shock Response; Human; Human Characteristics; Immune; Immune response; Immunosuppression; Impaired cognition; Incidence; Inflammation; Inflammatory; Intervention; Mediating; Mental Depression; Microglia; Mission; Modeling; Motor; Multiple Sclerosis; Mus; Neurologic; Patient Care; Patients; Pharmaceutical Preparations; Powder dose form; Prevention strategy; Preventive; Production; Property; Quality of life; Relapse; Reporting; Research Design; Respondent; Services; Severities; Signal Transduction; Supplementation; Symptoms; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Veterans; cognitive function; cost; cytokine; daily functioning; depressive symptoms; design; dietary supplements; disability; feeding; immune function; improved; mouse model; neuroinflammation; neuroprotection; novel; prevent; prospective; protective effect; rehabilitation strategy; response; treatment strategy

DESCRIPTION (provided by applicant): Diet therapy may provide a low cost alternative and/or adjuvant treatment to improve the care of veterans suffering from service-connected Multiple Sclerosis (MS). Botanicals are protective in MS animal models by modulating immune function and decreasing inflammation. Some also improve cognition and depression in animals, symptoms that are troublesome for the MS patient. Blueberries, in particular, can alter immune function, decrease inflammation and alter expression of proinflammatory cytokines, thought to be responsible for some of the sickness behavior, such as depression, fatigue and cognitive dysfunction, in MS. We have shown that dietary supplementation with whole, freeze-dried blueberry powder (WBBP) decreased by greater than 50%, the incidence of symptoms in a mouse model of MS and significantly improved symptoms in blueberry-fed mice that did get sick. We hypothesize that blueberry powder will have a dose-dependent effect in both preventing and ameliorating clinical and depressive symptoms in EAE mice. The following specific aims will be used to test this hypothesis: This proposal is designed to establish the therapeutic potential of blueberries as a prospective supplement to reduce the severity of symptoms in MS patients. This will be accomplished by testing whole blueberry powder in several different models of EAE to represent the heterogeneous nature of human MS. Further, we will determine whether the mechanism(s) of previously described blueberry protection involves alteration of immune cell effector function. Specifically, we will test the following hypothesis: blueberry supplementation shifts EAE immune response from a Th1 to a Th2 response with subsequent decrease in neuroinflammation. This hypothesis will be tested in three specific aims: Specific Aim 1: Determine whether blueberry protection in chronic EAE is a result of altered immune cell effector function. This aim will determine whether blueberry protection is a result of a shift from Th1 to Th2 T cell profiles including altered cytokine production. Specific Aim 2: Determine whether blueberry is protective in relapsing-remitting EAE. This aim will allow us to test the potential preventive and ameliorative properties of blueberry supplementation. Specific Aim 3: Determine whether blueberry protective effects are due to alterations in the NFkB:IkB signaling system. NFkB activation mediates inflammatory activation in microglia and astrocytes; this aim will allow us to determine NFkB involvement in blueberry neuroprotection. In summary, these studies are designed to determine whether there is potential for blueberries to be used as a supplement to reduce the severity of MS in humans. It is highly significant because of the lack of adequate current strategies to improve the quality of life for MS patients. Development of this novel diet therapy may provide significant direct and/or synergistic benefits in the treatment of MS at low cost with few side effects. These studies are of particular significance to potential treatment of MS since even the best pharmacological interventions have significant side effect and may interact with multiple other MS medications. However, diet therapy is easily administered, well tolerated and has few side effects. PUBLIC HEALTH RELEVANCE: Approximately 20,000 MS patients were cared for by the VA in 2002 (Vollmer et al., 2002) at a cost of more than $2.2 million dollars over patient's lifetime (Whetten-Goldstein et al., 1998). However, these therapies are only partially effective (Lo et al, 2005) and do not address MS-associated cognitive dysfunction, fatigue and depression which cause significant disability and lessen quality of life (Bagert et al., 2002; Crayton and Rossman, 2006; Deloire et al., 2006; McCrone et al., 2008). Treatment strategies that improve these parameters as well as improve motor function would be greatly useful in helping MS patients maintain life quality (Hadjimichael et al., 2008) particularly if the strategy was without pharmacologic side effects and medication interactions. Diet therapy offers an inexpensive, easily administered, and well tolerated strategy with few side effects or medication interactions. It may improve or maintain daily function and quality of life in MS patients as well as improve motor function, factors of critical importance to the VA Patient Care Mission.

描述（由申请人提供）： 饮食疗法可以提供一种低成本的替代和/或辅助治疗，以改善患有与服役相关的多发性硬化症 (MS) 的退伍军人的护理。植物药通过调节免疫功能和减少炎症在多发性硬化症动物模型中发挥保护作用。有些还可以改善动物的认知能力和抑郁症，这些症状对多发性硬化症患者来说是麻烦的。尤其是蓝莓，可以改变免疫功能，减少炎症并改变促炎细胞因子的表达，这些细胞因子被认为是导致多发性硬化症的一些疾病行为的原因，例如抑郁、疲劳和认知功能障碍。我们已经证明，在膳食中添加完整的冻干蓝莓粉 (WBBP)，可使多发性硬化症小鼠模型中的症状发生率降低 50% 以上，并显着改善食用蓝莓喂养的患病小鼠的症状。我们假设蓝莓粉在预防和改善 EAE 小鼠的临床症状和抑郁症状方面具有剂量依赖性作用。以下具体目标将用于检验这一假设： 该提案旨在确定蓝莓作为一种前瞻性补充剂的治疗潜力，以减轻多发性硬化症患者症状的严重程度。这将通过在几种不同的 EAE 模型中测试整个蓝莓粉来实现，以代表人类 MS 的异质性。此外，我们将确定先前描述的蓝莓保护机制是否涉及免疫细胞效应器功能的改变。具体来说，我们将测试以下假设：蓝莓补充剂将 EAE 免疫反应从 Th1 反应转变为 Th2 反应，随后神经炎症减少。该假设将通过三个具体目标进行检验： 具体目标 1：确定蓝莓对慢性 EAE 的保护作用是否是免疫细胞效应器功能改变的结果。这一目标将确定蓝莓保护是否是从 Th1 型 T 细胞谱向 Th2 型 T 细胞谱转变（包括细胞因子产生改变）的结果。具体目标 2：确定蓝莓是否对复发缓解型 EAE 具有保护作用。这一目标将使我们能够测试蓝莓补充剂的潜在预防和改善特性。具体目标 3：确定蓝莓的保护作用是否是由于 NFkB:IkB 信号系统的改变所致。 NFkB 激活介导小胶质细胞和星形胶质细胞的炎症激活；这一目标将使我们能够确定 NFkB 参与蓝莓神经保护作用。总之，这些研究旨在确定蓝莓是否有可能作为补充剂来降低人类多发性硬化症的严重程度。这是非常重要的，因为目前缺乏足够的策略来改善多发性硬化症患者的生活质量。这种新型饮食疗法的开发可能会以低成本、很少副作用的方式为多发性硬化症的治疗提供显着的直接和/或协同效益。这些研究对于多发性硬化症的潜在治疗具有特别重要的意义，因为即使是最好的药物干预措施也会产生显着的副作用，并且可能与多种其他多发性硬化症药物相互作用。然而，饮食疗法易于实施、耐受性良好且副作用很少。 公共卫生相关性： 2002 年，大约 20,000 名多发性硬化症患者接受了 VA 的护理（Vollmer 等人，2002 年），患者一生的费用超过 220 万美元（Whetten-Goldstein 等人，1998 年）。然而，这些疗法仅部分有效（Lo 等人，2005 年），并且不能解决 MS 相关的认知功能障碍、疲劳和抑郁问题，这些功能障碍会导致严重残疾并降低生活质量（Bagert 等人，2002 年；Crayton 和 Rossman，2006 年） ；德洛伊尔等人，2006；麦克龙等人，2008）。改善这些参数以及改善运动功能的治疗策略将非常有助于帮助多发性硬化症患者维持生活质量（Hadjimichael 等，2008），特别是如果该策略没有药理副作用和药物相互作用。饮食疗法提供了一种廉价、易于管理且耐受性良好的策略，且副作用或药物相互作用很少。它可以改善或维持多发性硬化症患者的日常功能和生活质量，并改善运动功能，这些对于 VA 患者护理任务至关重要。