Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra (SN). Among the many pathogenic mechanisms thought to contribute to the demise of these cells, dopamine-dependent oxidative stress has classically taken center stage due to extensive experimental evidence showing that dopamine-derived reactive oxygen species and oxidized dopamine metabolites are toxic to nigral neurons. In recent years, however, the involvement of neuro-inflammatory processes in nigral degeneration has gained increasing attention. Not only have activated microglia and increased levels of inflammatory mediators been detected in the striatum of deceased PD patients, but a large body of animal studies points to a contributory role of inflammation in dopaminergic cell loss. Recently, postmortem examination of human subjects exposed to the parkinsonism-inducing toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), revealed the presence of activated microglia decades after drug exposure, suggesting that even a brief pathogenic insult can induce an ongoing inflammatory response. Perhaps not surprisingly, non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of developing PD. In the past few years, various pathways have come to light that could link dopamine-dependent oxidative stress and microglial activation, finally ascribing a pathogenic trigger to the chronic inflammatory response characteristic of PD.

Keywords: Parkinson's disease; Inflammation; Oxidative stress; Microglia; Cytokines; Dopamine

Abbreviations: CNS, central nervous system; COX-2, cyclooxygenase-2; DOPAC, dihydroxyphenylacetic acid; DOPALD, dihydroxyphenylacetaldehyde; eNOS, endothelial NOS; GSH, glutathione; HNE, 4-hydroxy-2,3-nonenal; IFN-γ, interferon-gamma; IL, interleukin; iNOS, inducible NOS; LPS, lipo-polysaccharide; MAO, monoamine oxidase; MPP⁺, 1-methyl-4-phenylpyridium ions; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; nNOS, neuronal NOS; NOS, NO-synthase; NSAIDs, non-steroidal anti-inflammatory drugs; PD, Parkinson's disease; PHOX, phagocyte oxidase; RNS, reactive nitrogen species; ROS, reactive oxygen species; SN, substantia nigra; SNpc, substantia nigra pars compacta; TH, tyrosine hydroxylase; UPS, ubiquitin proteasomal system

Article Outline

Brain inflammation

Role of microglia in brain inflammation

Clinical characteristics of Parkinson's disease

Molecular pathways of neurodegeneration in Parkinson's disease

Dopamine-dependent oxidative stress: evidence and implications

Evidence of oxidative stress in PD

Linking dopamine to mitochondrial dysfunction

Linking dopamine to defective proteolysis

The role of inflammation in Parkinson's disease

Microglial-mediated inflammation and neurotoxicity

Dopamine and activation of microglia: is there a link?

The effect of anti-inflammatory drugs in Parkinson's disease

A vicious cycle

Acknowledgements

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