Role of Specialized Pro-resolving Mediators in Reducing Neuroinflammation in Neurodegenerative Disorders

Abstract

Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative disorders that affect millions of individuals worldwide. As incidence of these conditions increases with age, there will undoubtedly be an increased prevalence of cases in the near future. Neuroinflammation is a hallmark in the development and progression of neurodegenerative diseases and prevention or resolution of chronic neuroinflammation may represent a novel approach to treatment. The present review highlights the potential of the anti-inflammatory and pro-resolving effects of polyunsaturated fatty acid (PUFA)-derived mediators (Specialized Pro-resolving Mediators-SPM) in neurodegenerative disorders. PUFA-derived SPM are biosynthesized in response to chemicals produced from acute inflammatory responses. Preclinical studies from both AD and PD models suggest a dysregulation of SPM and their receptors in neurological disorders. Decreased SPM may be due to inadequate substrate, an imbalance between SPM and pro-inflammatory mediators or a disruption in SPM synthesis. SPMs hold great promise for neuroprotection in AD by altering expression of pro-inflammatory genes, modulating macrophage function, serving as a biomarker for AD status, and promoting resolution of neuroinflammation. In PD, data suggest SPM are able to cross the blood-brain barrier, inhibit microglial activation and decrease induced markers of inflammation, possibly as a result of their ability to downregulate NFκB signaling pathways. Several in vivo and in vitro studies suggest a benefit from administration of SPMs in both neurodegenerative disorders. However, extrapolation of these outcomes to humans is difficult as no models are able to replicate all features of AD or PD. Minimal data evaluating these PUFA-derived metabolites in humans with neurodegenerative disorders are available and a gap in knowledge exists regarding behavior of SPM and their receptors in patients with these conditions. There is also large gap in our knowledge regarding which lipid mediator would be most effective in which model of AD or PD and how dietary intake or supplementation can impact SPM levels. Future direction should include focused, translational efforts to investigate SPM as an add-on (in addition to standard treatment) or as standalone agents in patients with neurodegenerative disorders.

Keywords: Alzheimer’s disease; Parkinson’s disease; neurodegenerative disorder; neuroinflammation; omega-3 fatty acids; omega-6 fatty acid; polyunsaturated fatty acids; specialized pro-resolving lipid mediator (SPM).

FIGURE 1

Specialized pro-resolving mediators (SPM) and their receptors. These SPM are derived from omega (n)-3 and n-6 polyunsaturated fatty acids (PUFAS) in response to chemicals produced from acute inflammatory responses. ALX/FPR2, formyl peptide receptor 2; LXA4, lipoxin A4; GPR32, G protein-coupled receptor 32; RvD1, resolvin D1; GPR18, G protein-coupled receptor 18; RvD2, resolvin D2; ChemR23, chemerin receptor 23; RvE1, resolvin E1; COX-2, cyclooxygenase-2; LOX, lipoxygenase; MaR1, maresin 1; NPD/DP1, neuroprotectin/protectin D1.