Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Abstract

Inflammation, a self-defensive reaction against various pathogenic stimuli, may become harmful self-damaging process. Increasing evidence has linked chronic inflammation to a number of neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis. In the central nervous system, microglia, the resident innate immune cells play major role in the inflammatory process. Although they form the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly toxic to neurons by releasing various substances such as inflammatory cytokines (IL-1β, TNF-α, IL-6), NO, PGE2, and superoxide. Moreover, our recent study demonstrated that activated microglia phagocytose not only damaged cell debris but also neighboring intact cells. It further supports their active participation in self-perpetuating neuronal damaging cycles. In the following review, we discuss microglial responses to damaging neurons, known activators released from injured neurons and how microglia cause neuronal degeneration. In the last part, microglial activation and their role in PD are discussed in depth.

Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson's disease

“…Microglia, the resident immune cells in the brain (del Rio-Hortega 1993), can become overactivated by direct stimulation of microglia and neuronal damage and consequent reactive microgliosis ). Since activated microglial cells are important sources of proinflammatory cytokines such as TNF-a, IL-1b, and IFN-g, reactive microgliosis could be an underlying mechanism of progressive neurodegeneration in PD (Kim & Joh 2006). Previous studies reported that SNpc microglial activation was detected as early as 12 h and reached a maximum 1 day after MPTP injection; it subsided to control levels in about a week (Liberatore et al 1999, Dehmer et al 2000.…”

“…Since microglia are a principal source of a variety of cytotoxic compounds, including reactive oxygen species, reactive nitrogen species, pro-inflammatory cytokines, and prostaglandins (Banati et al 1993); microglial activation is known to play a key role in the pathogenesis of human PD and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model (Vila et al 2001). Several molecules released from stressed dopaminergic neurons, such as a-synuclein, neuromelanin, and matrix metalloproteinase-3 (MMP-3), are found to be involved in microglial activation (Kim et al 2005, Kim & Joh 2006. Among these microglial activators, MMP-3 is known to be responsible for the activation of microglia and the release of NADPH oxidase-derived superoxide and nuclear factor-kB-mediated pro-inflammatory cytokines, and eventually exacerbates dopaminergic neurodegeneration.…”

Parkinson's disease and pesticides: a toxicological perspective

“…The damage reported in these studies was seen in the striatum first, followed by the SNpc (this is similar to the 'dying-back' phenomenon in PD); however, these changes were seen only in a subset of exposed animals. Additionally, increased oxidative stress, ubiquitin accumulation, proteasomal inhibition and inflammation all have been observed in response to rotenone exposure [19,[48][49][50]. Despite this evidence of a role for rotenone in PD pathogenesis, it is unlikely the rotenone is a major contributor because of its limited commercial use, short half-life in the environment and low bioavailability.…”

An efficient method to limit microglia-dependent effects in astroglial cultures

“…Microglia, the most reactive cells against pro-inflammatory stimuli, detect and respond rapidly to pro-inflammatory triggers (Lull and Block, 2010;Kim and Joh, 2006). Based on previous papers, astrocyte-mediated effects are completely masked when cultures contain a large population of microglia.…”