The Anti-Inflammatory Role of Omega-3 Polyunsaturated Fatty Acids Metabolites in Pre-Clinical Models of Psychiatric, Neurodegenerative, and Neurological Disorders

Abstract

Inflammation has been identified as one of the main pathophysiological mechanisms underlying neuropsychiatric and neurodegenerative disorders. Despite the role of inflammation in those conditions, there is still a lack of effective anti-inflammatory therapeutic strategies. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) can reduce depressive symptoms and exert anti-inflammatory action putatively by the production of distinct n-3 PUFA-derived metabolites, such as resolvins D (RvD) and E (RvE) series, maresins (MaR) and protectins (PD), which are collectively named specialized pro-resolving mediators (SPMs) and act as strong anti-inflammatory agents. In this review we summarize evidence showing the effects of treatment with those metabolites in pre-clinical models of psychiatric, neurodegenerative and neurological disorders. A total of 25 pre-clinical studies were identified using the PubMed database. Overall, RvD and RvE treatment improved depressive-like behaviors, whereas protectins and maresins ameliorated neurological function. On a cellular level, RvDs increased serotonin levels in a model of depression, and decreased gliosis in neurodegenerative disorders. Protectins prevented neurite and dendrite retraction and apoptosis in models of neurodegeneration, while maresins reduced cell death across all studies. In terms of mechanisms, all SPMs down-regulated pro-inflammatory cytokines. Resolvins activated mTOR and MAP/ERK signaling in models of depression, while resolvins and maresins activated the NF-κB pathway in models of neurodegeneration and neurological disorders. Our review indicates a potential promising approach for tailored therapy with n-3 PUFAs-derived metabolites in the treatment of psychiatric, neurodegenerative, and neurological conditions.

Keywords: maresin; neuroinflammation; omega-3; polyunsaturated fatty acid; protectin; resolvin.

Figure 1

Metabolism of DHA and EPA to SPMs through enzymatic transformation. SPMs are produced upon metabolism of n-3 PUFAs by specific lipoxygenase and cyclooxygenase enzymes. Respectively, the enzymes 15-lipoxygenase-1 (15-LOX) and 12-lipoxygenase (12-LOX) are responsible for initiating the conversion of DHA to protectin-1 (PD1), and maresin 1 and 2 (MaR1, MaR2), whereas 15-LOX, cyclooxygenase 2 (COX-2) and cytochrome P450 are responsible for the conversion of DHA to resolvins D series (RvD), and of EPA to resolvins E series (RvE). Downstream, metabolism of RvD and RvE are dependent on 5-lipoxygenase (5-LOX). Aspirin-acetylated COX-2 followed by 5-lipoxygenase (5-LOX) transformation generates aspirin-triggered isomers of RvDs (AT-RvD).

Figure 2

Comparison of behavioral, cellular, and molecular findings upon treatment with SPMs in the context of psychiatric, neurodegenerative, and neurological disorders. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; MAP/ERK, mitogen-activated protein kinases/extracellular signal-regulated kinases; MaR, maresin; mTORC, mammalian target of rapamycin complex; NF-κB, Nuclear factor-kappa B; PD, protectin; PI3K/Akt, Phosphoinositide 3-kinases/Protein kinase B; RvD, resolvins D series; RvE, resolvins E series. ↗ increase; ↘ decrease.