The Effect of Docosahexaenoic Acid in a Mouse Model of Neuroinflammation

Several studies have shown that dietary omega-3 polyunsaturated fatty acids (n-3 PUFA) are beneficial in neurodegenerative diseases, although the mechanism of action is not agreed upon. Because most neurodegenerative diseases have an inflammatory component, it is possible that docosahexaenoic acid (DHA) is anti-inflammatory in the brain as it is known to be in several non-neural tissues. Specialized pro-resolving mediators (SPM) are metabolized from DHA and are leading candidates to explain the anti-inflammatory effects of DHA. The goal of this work was to investigate the role and potential mechanisms of action of DHA in neuroinflammation. In our first approach, fat-1 transgenic mice had higher phospholipid and unesterified DHA levels in their hippocampi, and attenuated lipopolysaccharide (LPS)-induced neuroinflammation, compared to wildtype littermates. Feeding wildtype littermates n-3 PUFA mimicked hippocampal DHA levels and LPS-induced neuroinflammatory responses of fat-1 mice, indicating DHA is anti-neuroinflammatory whether derived from the diet or the activity of the fat-1 protein. In an attempt to further augment hippocampal DHA levels, feeding n-3 PUFA adequate mice an n-3 PUFA diet increased phospholipid but not unesterified DHA levels, and did not attenuate LPS-induced neuroinflammation, highlighting the potential importance of unesterified DHA. Directly infusing unesterified DHA into a cerebral ventricle throughout LPS-induced neuroinflammation mimicked several aspects of the attenuated neuroinflammatory response seen with our chronic dietary and transgenic models, as did infusing its 17S-hydroperoxy-DHA (17S-HpDHA) derivative, a precursor to SPM. The metabolism of DHA to SPM in the brain was found to be distinct from non-neural tissues, characterized by the presence of protectin D1 and maresin 1, and the absence of resolvin D1 or D2. Further, infusing 17S-HpDHA increased protectin D1 concurrent to attenuating neuroinflammation, suggesting protectin D1 is responsible for some of the anti-neuroinflammatory effects of DHA. In conclusion, DHA is anti-neuroinflammatory in a mouse model of neuroinflammation, in part, via its metabolism to SPM.Ph