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

 描述（由申请人提供）：饮食中补充ω-3脂肪酸和添加糖对化疗诱导的认知缺陷的影响摘要被诊断患有乳腺癌（BC）的妇女包括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，对多达30%的接受治疗的女性的语言流畅性，记忆力和处理速度产生不利影响。化疗引起的认知功能障碍的生物学基础知之甚少，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;维持小鼠高蔗糖饮食会加剧炎症。在BC幸存者中，我们的数据表明，不健康的（即高添加糖）饮食会增加化疗后的全身炎症。补充omega-3脂肪酸（n-3 FAs）是减少炎症和解决改变生活的认知副作用的有希望的策略，原因有几个：n-3 FAs减少啮齿动物模型中的炎性细胞因子和脂质过氧化，改善一些老年人的认知，并且已经确定了化疗的安全性和耐受性。然而，饮食中添加的大量糖可能会干扰n-3 FAs的抗炎作用。该提案的主要目的是使用随机安慰剂对照试验来确定饮食补充n-3 FAs在多大程度上减少了神经炎症并防止BC手术后接受化疗的女性认知能力下降，以及n-3 FAs是否对通常饮食中添加糖较低的女性更有效。此外，我们将研究化疗损害认知能力的机制，以及添加糖改变n-3 FA神经保护作用的潜力，包括使用翻译小鼠模型的实验，该模型非常接近通常用于治疗BC女性的化疗方案。我们假设低糖/高n-3 FA饮食将减少神经炎症，减少炎症细胞因子和小鼠脑巨噬细胞（小胶质细胞）的激活，这反过来又会减轻化疗诱导的认知缺陷。我们进一步假设，n-3 FA补充剂将减少BC女性化疗的认知副作用，并且在饮食中消耗较低水平添加糖的女性中，副作用的减少将更大。了解化疗引起认知变化的机制，添加糖的潜在加重作用，以及用n-3 FAs干预以缓解这些缺陷是建立有效预防化疗诱导的认知功能障碍的策略的必要的第一步，这可以大大改善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.