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.
Highlights
Neuroinflammation is one of the hallmarks of Parkinson’s disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration
Our findings reveal that boosting the resolution of inflammation can prevent early α-syn-induced neuroinflammation, neurophysiological and motor deficits, suggesting that resolvins could be therapeutically exploited as novel diagnostic biomarkers and disease-modifying agents
Given that α-syn overexpression is pathogenic in PD and other synucleinopathies, we first characterized the very early effects of α-syn overexpression on the midbrain DA system, to highlight factors that contribute to DA neuron dysfunction and to cell death
Summary
Neuroinflammation is one of the hallmarks of Parkinson’s disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. 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). The SNpc shows high density of microglia[18,19] but evidence from experimental models suggest that DA neurons are highly and selectively vulnerable to inflammatory attacks[19,20,21,22], supporting the hypothesis that the microglia-mediated neuroinflammation contributes to the cascade of events that lead to degeneration and worsening of the disease[12,23]. The effect of modulating such neuroinflammatory circuits, in order to reverse or slow down the disease progression, is yet unexplored
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