Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease

Abstract

Neuroinflammation is one of the hallmarks of Parkinson’s disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. Recent studies link chronic inflammation with failure to resolve early inflammation, a process operated by specialized pro-resolving mediators, including resolvins. However, the effects of stimulating the resolution of inflammation in PD – to modulate disease progression – still remain unexplored. Here we show that rats overexpressing human α-synuclein (Syn) display altered DA neuron properties, reduced striatal DA outflow and motor deficits prior to nigral degeneration. These early alterations are coupled with microglia activation and perturbations of inflammatory and pro-resolving mediators, namely IFN-γ and resolvin D1 (RvD1). Chronic and early RvD1 administration in Syn rats prevents central and peripheral inflammation, as well as neuronal dysfunction and motor deficits. We also show that endogenous RvD1 is decreased in human patients with early-PD. Our results suggest there is an imbalance between neuroinflammatory and pro-resolving processes in PD.

Specialized pro-resolving lipid mediators are differentially altered in peripheral blood of patients with multiple sclerosis and attenuate monocyte and blood-brain barrier dysfunction

“…In line with the general concepts that bioactive lipid mediators undergo temporal and spatial production during inflammation, that SPMs appear at the peak of acute inflammation in order to later reduce inflammation by activating endogenous resolution programs (7,10) and that chronic inflammation may result from failed resolution mechanisms (12,13), our results display that during the acute phase of the disease (relapsing form) there is an imbalance between pro-inflammatory and proresolving lipid mediators, in favor of the former, and an insufficient or lack of expression of many key SPMs (including E-resolvins, maresins and the rest of Dresolvins), which may in turn affect the outcome of remission and thereby, in theory and yet to be fully elucidated in further studies, even lead to disease progression.…”

Proteostasis of α-Synuclein and Its Role in the Pathogenesis of Parkinson’s Disease

“…Different forms of α-Synuclein exhibit distinct effects in triggering microglial phagocytosis and inflammation. Rather than oligomers of α-Synuclein which only induce upregulation of IL-1β (Krashia et al, 2019), fibrillar α-Synuclein is able to elicit strong pro-inflammatory responses in a microglial cell line (Gustot et al, 2015;Hoffmann et al, 2016;Zhou et al, 2016). Fibrillar α-Synuclein can activate NLRP3 inflammasome which leads to the cleaving of pro-inflammatory cytokines, such as IL-1β and IL-18 (Zhou et al, 2016;Chatterjee et al, 2020;Haque et al, 2020).…”

“…Fibrillar α-Synuclein can activate NLRP3 inflammasome which leads to the cleaving of pro-inflammatory cytokines, such as IL-1β and IL-18 (Zhou et al, 2016;Chatterjee et al, 2020;Haque et al, 2020). Also, using a rat model that overexpresses human α-Synuclein, Krashia et al found that α-Synuclein-induced inflammation precedes nigral degeneration, and administration of resolving D1, a potent lipid mediator that can resolve inflammation to promote restoration of tissue homeostasis, prevents neuronal dysfunction and motor deficits (Krashia et al, 2019). Multiple receptors and pathways are responsible for inducing pro-inflammatory responses in microglia in PD ( Table 1).…”

n-3 Polyunsaturated Fatty Acids and Their Derivates Reduce Neuroinflammation during Aging

“…RvD1 promotes Aβ phagocytosis by macrophages isolated from Alzheimer's patients, reducing the amyloid load [151,152]. Moreover, as cited in Krashia et al, endogenous RvD1 is decreased in patients diagnosed with early-Parkinson's disease [153]. As a result, the decrease of RvD1 levels in Alzheimer's and Parkinson's disease patient's brain could contribute to the disease development and progression.…”

“…Moreover, RvD1 induces the polarization of macrophages and microglia toward an M2 phagocytic phenotype [161][162][163]. Chronic and early RvD1 administration in a rat model of Parkinson's disease prevents central and peripheral inflammation, as well as neuronal dysfunction and motor deficits [153]. In addition, the precursors of RvD1, 17R-HDHA and 17S-HDHA, reduce the production of pro-inflammatory cytokines in the spinal cord and in the hippocampus [135,164].…”