Oxidative stress and inflammation in Parkinson's disease: is there a causal link?
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.
Hald
Andreas
A
Department of Pharmacology, Danish University of Pharmaceutical Sciences, Jagtvej 160, 2200 Copenhagen, Denmark.
Lotharius
Julie
J
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D006801:Humans; D017628:Microglia / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D008959:Models, Neurological; D018384:Oxidative Stress / Q000502:physiology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*
D000893:Anti-Inflammatory Agents; D004298:Dopamine