Editors' ChoiceParkinson’s Disease

Resolvin-g Parkinson’s disease

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Science Translational Medicine  02 Oct 2019:
Vol. 11, Issue 512, eaaz3713
DOI: 10.1126/scitranslmed.aaz3713

Abstract

Resolvin D1 attenuates neuroinflammation in a rat model of Parkinson’s disease.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by tremor, rigidity, and slow movement. Hallmarks of disease include the loss of nerve cells in the substantia nigra of the brain, leading to impaired dopaminergic neurotransmission and aggregation of the α-synuclein (α-syn) protein in the form of Lewy bodies and Lewy neurites. Neuroinflammation is an established feature of PD. Like other chronic inflammatory diseases, neuroinflammation may arise from failure to resolve inflammation, a process which is mediated by specialized proresolving lipid mediators, a superfamily of inflammation-resolving lipids that derive metabolically from ω-3 and ω-6 essential fatty acids. However, the effects of promoting resolution of neuroinflammation remain underinvestigated.

Krashia and colleagues used a transgenic rat model of PD that overexpresses the human nonmutated α-syn (Syn rats) to investigate the interrelationship between α-syn load and neuroinflammation. First, they characterized the early effects of α-syn overexpression on the rat brain and dopaminergic system to determine whether neuroinflammatory changes were associated with proresolution deficits. They next investigated the effects of a proresolving mediator in Syn rats. Given that animal models of PD may not completely recapitulate the equivalent human disease, they also analyzed levels of proinflammatory and proresolving mediators in cerebrospinal fluid (CSF) and plasma from early stage patients with PD.

α-syn overexpression in Syn rats induced early alterations in dopamine neuron properties, dopaminergic transmission, and motor behavior. The authors identified a link between α-syn overexpression and neuroinflammation, showing a reduction of a specific proresolving mediator Resolvin D1 (RvD1). Treatment of Syn rats with RvD1 reduced neuroinflammation, restored dopaminergic neurotransmission, and prevented subsequent development of neuronal deficits and motor impairment. In patients with early PD, the authors found increased plasma expression of interferon-γ and interleukin-10 and reduced CSF and plasma content of RvD1 compared with age-matched subjects without degenerative inflammatory diseases.

The findings from this study support the critical involvement of inflammation in PD. The authors show that patients with early PD had central and peripheral RvD1 impairment, suggesting that RvD1 could be therapeutically exploited as diagnostic biomarker. Treatment with RvD1 promoted resolution of α-syn–induced neuroinflammation, ameliorating neurophysiological and motor deficits. These findings have so far been limited to a rat model, but they suggest translational potential for the development of proresolving therapies for human neuroinflammatory disease.

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