Effect of n-3 fatty acids and sugars on chemotherapy-induced cognitive deficits

 描述(申请人提供)：补充omega-3脂肪酸和饮食中添加的糖对化疗引起的认知障碍的影响摘要被诊断为乳腺癌(BC)的妇女是美国最大的癌症幸存者群体。用于治疗BC的化疗对大脑有潜在的毒副作用，在接受治疗的女性中，高达30%的人会对语言流畅性、记忆力和处理速度产生不利影响。化疗所致认知功能障碍的生物学基础尚不清楚，也没有有效的预防策略。我们的初步数据表明，化疗增加了氧化应激，这反过来又促进了小鼠模型中的神经炎症和认知变化；维持小鼠的高蔗糖饮食会加剧炎症。在不列颠哥伦比亚省的幸存者中，我们的数据表明，不健康(即高添加糖)的饮食会增加化疗后的全身炎症。补充omega-3脂肪酸(n-3 FA)是一种很有前途的策略，可以减少炎症和解决改变生活的认知副作用，原因有几个：n-3脂肪酸可以减少啮齿动物模型中的炎症细胞因子和脂质过氧化，改善一些老年人的认知能力，并建立了化疗的安全性和耐受性。然而，饮食中添加大量的糖可能会干扰n-3脂肪酸的抗炎作用。这项建议的主要目标是使用一项随机的安慰剂对照试验来确定在BC手术后接受化疗的女性中，饮食补充n-3脂肪酸在多大程度上减少了神经炎症和防止认知能力下降，以及n-3 FA是否对通常饮食中添加糖较低的女性更有效。此外，我们将通过使用与通常用于治疗女性BC的化疗方案非常相似的翻译小鼠模型进行实验，研究化疗损害认知能力和添加糖改变n-3脂肪酸神经保护作用的可能性的机制。我们假设，低糖/高n-3FA饮食将减少神经炎症，减少炎性细胞因子和小鼠脑巨噬细胞(小胶质细胞)的激活，这反过来将减轻化疗引起的认知障碍。我们进一步假设，补充n-3FA将减少患有BC的女性患者化疗的认知副作用，并且在饮食中摄入较低添加糖水平的女性，副作用的减少将更明显。了解化疗引起认知改变的机制、添加糖的潜在加重作用以及n-3脂肪酸的干预以缓解这些缺陷，是为化疗引起的认知功能障碍建立有效的预防策略的必要的第一步，这将极大地提高癌症幸存者的生活质量。

 DESCRIPTION (provided by applicant): Effect of omega-3 fatty acid supplementation and added sugars in the diet on chemotherapy-induced cognitive deficits Abstract Women diagnosed with breast cancer (BC) comprises the largest group of cancer survivors in the United States. Chemotherapy used to treat BC has potentially toxic side effects in the brain, adversely affecting verbal fluency, memory and processing speed in up to 30% of women treated. The biological basis of chemotherapy induced cognitive dysfunction is poorly understood and no effective preventative strategies exist. Our preliminary data illustrate that chemotherapy increases oxidative stress, which in turn promotes neuroinflammation and cognitive changes in a mouse model; maintaining mice on high sucrose diets exacerbates the inflammation. In BC survivors, our data suggest that an unhealthy (i.e. high added sugar) diet increases systemic inflammation post-chemotherapy. Supplementing with omega-3 fatty acids (n-3 FAs) is a promising strategy to decrease inflammation and address life-altering cognitive side effects for several reasons: n-3 FAs reduce inflammatory cytokines and lipid peroxidation in rodent models, improve cognition in some older adults, and have established safety and tolerability with chemotherapy. However, high amounts of added sugars in the diet may interfere with the anti-inflammatory effects of n-3 FAs. The primary objective of this proposal is to use a randomized placebo controlled trial to determine the extent to which dietary supplementation with n-3 FAs reduces neuroinflammation and prevents cognitive decline in women receiving chemotherapy after BC surgery, and whether n-3 FAs are more effective in women whose usual diets are lower in added sugars. In addition, we will examine the mechanisms through which chemotherapy impairs cognitive performance and the potential of added sugars to modify the neuroprotective effects of n-3 FAs by including experiments using a translational mouse model that closely approximates the chemotherapy regimen commonly used to treat women with BC. We hypothesize that a low sugar/high n-3 FA diet will reduce neuroinflammation, decreasing inflammatory cytokines and activation of brain macrophages (microglia) in mice, which in turn will lessen chemotherapy-induced cognitive deficits. We further hypothesize that n-3 FA supplementation will decrease the cognitive side effects of chemotherapy in women with BC, and that the reduction in side effects will be greater in women who consume lower levels of added sugars in the diet. Understanding the mechanisms by which chemotherapy causes cognitive changes, the potential exacerbating role of added sugars, and intervening with n-3 FAs to alleviate these deficits are the necessary first steps in establishing an effective preventative strategy for chemotherapy-induced cognitive dysfunction, which could vastly improve quality of life for cancer survivors.