Neuroinflammation in Parkinson's disease and its potential as therapeutic target

Abstract

Parkinson's disease (PD), the second most common age-associated neurodegenerative disorder, is characterized by the loss of dopaminergic (DA) neurons and the presence of α-synuclein-containing aggregates in the substantia nigra pars compacta (SNpc). Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Post-mortem analyses of human PD patients and experimental animal studies indicate that activation of glial cells and increases in pro-inflammatory factor levels are common features of the PD brain. Chronic release of pro-inflammatory cytokines by activated astrocytes and microglia leads to the exacerbation of DA neuron degeneration in the SNpc. Besides, peripheral immune system is also implicated in the pathogenesis of PD. Infiltration and accumulation of immune cells from the periphery are detected in and around the affected brain regions of PD patients. Moreover, inflammatory processes have been suggested as promising interventional targets for PD and even other neurodegenerative diseases. A better understanding of the role of inflammation in PD will provide new insights into the pathological processes and help to establish effective therapeutic strategies. In this review, we will summarize recent progresses in the neuroimmune aspects of PD and highlight the potential therapeutic interventions targeting neuroinflammation.

Keywords: Glial cells; Neurodegeneration; Neuroinflammation; Parkinson’s disease.

Fig. 1

Diagrammatic representation of inflammatory mechanisms involved in PD pathogenesis. Microglia become activated M1 phenotype in PD under pathological conditions such as protein aggregation, gene mutations, environmental factors and cytokines released from infiltrated T cells. The pro-inflammatory mediators from M1 microglia activate astrocytes leading to elevated production of proinflammatory factors, nitric oxide and superoxide radical, contributing to degeneration of DA neurons. The molecules released from degenerative DA neurons can further cause activation of glia and enhanced inflammatory response. At certain stage of PD, subpopulation of microglia may become activated M2 phenotype releasing anti-inflammatory factors, including TGF-β, and exert a neuroprotective effect in PD