Inflammation in Parkinson's disease: causative or epiphenomenal?
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra (SN). Several pathogenic mechanisms have been implicated in the demise of these cells, including dopamine-dependent oxidative stress, mitochondrial dysfunction, excitotoxicity, and proteasomal impairment. In recent years, the involvement of neuroinflammatory 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 PD patients, but a large body of animal studies points to a contributory role of inflammation in dopaminergic cell loss. For example, post-mortem examination of human subjects exposed to the parkinsonism-inducing toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 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, nonsteroidal anti-inflammatory drugs have been shown to reduce the risk of developing PD. In the past few years, various pathways have come to light that could link neurodegeneration and microglial activation, finally ascribing a pathogenic trigger to the chronic inflammatory response characteristic of PD.
Hald
Andreas
A
Department of Pharmacology and Pharmacotherapeutics, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark.
Van Beek
Johan
J
Lotharius
Julie
J
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D002908:Chronic Disease; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D020267:MPTP Poisoning / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D012307:Risk Factors; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine