Department of Nutritional Sciences, University of Toronto, Toronto, Canada.
J Neurochem. 2013 Nov;127(3):378-93. doi: 10.1111/jnc.12392. Epub 2013 Aug 28.
Docosahexaenoic acid (22:6n-3) is the major brain n-3 polyunsaturated fatty acid and it is possible that docosahexaenoic acid is anti-inflammatory in the brain as it is known to be in other tissues. Using a combination of models including the fat-1 transgenic mouse, chronic dietary n-3 polyunsaturated fatty acid modulation in transgenic and wild-type mice, and acute direct brain infusion, we demonstrated that unesterified docosahexaenoic acid attenuates neuroinflammation initiated by intracerebroventricular lipopolysaccharide. Hippocampal neuroinflammation was assessed by gene expression and immunohistochemistry. Furthermore, docosahexaenoic acid protected against lipopolysaccharide-induced neuronal loss. Acute intracerebroventricular infusion of unesterified docosahexaenoic acid or its 12/15-lipoxygenase product and precursor to protectins and resolvins, 17S-hydroperoxy-docosahexaenoic acid, mimics anti-neuroinflammatory aspects of chronically increased unesterified docosahexaenoic acid. LC-MS/MS revealed that neuroprotectin D1 and several other docosahexaenoic acid-derived specialized pro-resolving mediators are present in the hippocampus. Acute intracerebroventricular infusion of 17S-hydroperoxy-docosahexaenoic acid increases hippocampal neuroprotectin D1 levels concomitant to attenuating neuroinflammation. These results show that unesterified docosahexaenoic acid is protective in a lipopolysaccharide-initiated mouse model of acute neuroinflammation, at least in part, via its conversion to specialized pro-resolving mediators; these docosahexaenoic acid stores may provide novel targets for the prevention and treatment(s) of neurological disorders with a neuroinflammatory component. Our study shows that chronically increased brain unesterified DHA levels, but not solely phospholipid DHA levels, attenuate neuroinflammation. Similar attenuations occur with acute increases in brain unesterified DHA or 17S-HpDHA levels, highlighting the importance of an available pool of precursor unesterified DHA for the production of enzymatically derived specialized pro-resolving mediators that are critical in the regulation of neuroinflammation.
二十二碳六烯酸（22:6n-3）是大脑中主要的 n-3 多不饱和脂肪酸，并且已知二十二碳六烯酸在其他组织中具有抗炎作用，因此它在大脑中可能具有抗炎作用。通过使用包括 fat-1 转基因小鼠在内的多种模型，对转基因和野生型小鼠进行慢性饮食 n-3 多不饱和脂肪酸调节，以及急性直接脑内输注，我们证明了未酯化的二十二碳六烯酸可减轻脑室内内毒素脂多糖引发的神经炎症。通过基因表达和免疫组织化学评估海马神经炎症。此外，二十二碳六烯酸可防止脂多糖诱导的神经元丢失。急性脑室内输注未酯化的二十二碳六烯酸或其 12/15-脂氧合酶产物和保护素和 resolvin 的前体 17S-过氧-二十二碳六烯酸，可模拟慢性增加的未酯化二十二碳六烯酸的抗炎作用。LC-MS/MS 显示，神经保护素 D1 和其他几种二十二碳六烯酸衍生的专门的促解决介质存在于海马体中。急性脑室内输注 17S-过氧-二十二碳六烯酸可增加海马神经保护素 D1 水平，同时减轻神经炎症。这些结果表明，未酯化的二十二碳六烯酸在脂多糖诱导的急性神经炎症的小鼠模型中具有保护作用，至少部分是通过其转化为专门的促解决介质；这些二十二碳六烯酸储存可能为具有神经炎症成分的神经退行性疾病的预防和治疗提供新的靶点。我们的研究表明，慢性增加大脑未酯化的 DHA 水平，而不仅仅是磷脂 DHA 水平，可减轻神经炎症。急性增加大脑未酯化的 DHA 或 17S-HpDHA 水平也会发生类似的衰减，这突出了可利用的未酯化 DHA 前体池对于酶衍生的专门的促解决介质的产生的重要性，而这些介质对于神经炎症的调节至关重要。
