N-3 Polyunsaturated Fatty Acids and the Resolution of Neuroinflammation

Abstract

In the past few decades, as a result of their anti-inflammatory properties, n-3 long chain polyunsaturated fatty acids (n-3 LC-PUFAs), have gained greater importance in the regulation of inflammation, especially in the central nervous system (in this case known as neuroinflammation). If sustained, neuroinflammation is a common denominator of neurological disorders, including Alzheimer's disease and major depression, and of aging. Hence, limiting neuroinflammation is a real strategy for neuroinflammatory disease therapy and treatment. Recent data show that n-3 LC-PUFAs exert anti-inflammatory properties in part through the synthesis of specialized pro-resolving mediators (SPMs) such as resolvins, maresins and protectins. These SPMs are crucially involved in the resolution of inflammation. They could be good candidates to resolve brain inflammation and to contribute to neuroprotective functions and could lead to novel therapeutics for brain inflammatory diseases. This review presents an overview 1) of brain n-3 LC-PUFAs as precursors of SPMs with an emphasis on the effect of n-3 PUFAs on neuroinflammation, 2) of the formation and action of SPMs in the brain and their biological roles, and the possible regulation of their synthesis by environmental factors such as inflammation and nutrition and, in particular, PUFA consumption.

Keywords: docosahexaenoic acid; eicosapentaenoic acid; n-3 long-chain PUFAs; neuroinflammation; nutrition; resolvins; specialized pro-resolving mediators.

Figure 1

Molecular events implicated in inflammation and the resolution of inflammation. AA, arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; IL, interleukin; TGF, transforming growth factor; TNF, tumor necrosis factor.

Figure 2

Main synthesis pathway of n-3 long-chain PUFA-derived lipid mediators. ALX/FpR2, lipoxin A4 receptor/formyl peptide receptor 2; BLT1, Leukotriene B4 receptor 1; ChemR23, chemokine-like receptor 1; COX-2, cyclooxygenase-2; CYP450, monoxygenases cytochrome P450; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GPR, G protein-coupled receptor; HDHA, hydroxy-docosahexaenoic acid; HEPE, hydroxy-eicosapentaenoic acid; HpDHA, hydroperoxyl-docosahexaenoic acid; HpEPE, hydroperoxy-eicosapentaenoic acid; LOX, lipoxygenases; PLA2, phospholipase A2.

Figure 3

Biochemical structures of the main n-3 long-chain PUFA-derived lipid mediators. DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HpDHA, hydroperoxyl-docosahexaenoic acid; HpEPE, hydroperoxy-eicosapentaenoic acid; Mar1, maresin 1; NPD1, neuroproetectin D1; RvD1, resolvin D1; RvE1, resolvin E1. (Serhan and Petasis, 2011; Serhan et al., 2015)

Figure 4

Regulation of n-3 long-chain PUFA-derived SPMs by PUFA consumption and inflammation. IL, interleukine; LPS, lipopolysaccharides; PUFA, polyunsaturated fatty acids; SPM, specialized pro-resolving mediators; TNF, tumor necrosis factor.