Abstract
BackgroundInflammatory processes are increased in the Parkinson's disease (PD) brain. The long-term use of nonsteroidal anti-inflammatory drugs has been associated, in retrospective studies, with decreased risk for PD, suggesting that inflammation may contribute to development of this disorder. The objective of this study was to determine the extent of complement activation, a major inflammatory mechanism, in PD.MethodsSubstantia nigra specimens from young normal subjects (n = 11–13), aged normal subjects (n = 24–28), and subjects with PD (n = 19–20), Alzheimer's disease (AD; n = 12–13), and dementia with Lewy bodies (DLB; n = 9) were stained for iC3b and C9, representing early- and late-stage complement activation, respectively. Numbers of iC3b+, C9+, and total melanized neurons in each section were counted in a blinded fashion. Nonparametric analyses were used to evaluate differences between groups and to evaluate correlations between complement staining, numbers of melanized neurons, and the duration of PD.ResultsLewy bodies in both PD and DLB specimens stained for iC3b and C9. Staining was also prominent on melanized neurons. The percentage of iC3b+ neurons was significantly increased in PD vs. aged normal and AD specimens, and in young normal vs. aged normal specimens. C9 immunoreactivity was significantly increased in PD vs. AD specimens, but unlike iC3b, the increased C9 staining in PD and young normal specimens did not achieve statistical significance vs. aged normal specimens. iC3b and C9 staining in PD specimens was not correlated with the numbers of remaining melanized neurons, nor with the duration of PD.ConclusionComplement activation occurs on Lewy bodies and melanized neurons in the PD substantia nigra. Early complement activation (iC3b) is increased on melanized neurons in PD vs. aged normal specimens, and late-stage complement activation (C9) also tends to increase. This latter finding suggests that complement activation may contribute to loss of dopaminergic neurons in some individuals with PD. Complement activation on melanized neurons appears to decrease with normal aging, suggesting a possible neuroprotective role for this process in the normal substantia nigra.
Highlights
Inflammatory processes are increased in the Parkinson's disease (PD) brain
Two retrospective studies indicated an association between the long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) and decreased risk for PD [10,11], suggesting that inflammation may be important in the development of this disorder; a third retrospective study found no evidence for protective effects of NSAIDs against PD [12]
Yamada et al [21] reported staining of Lewy bodies in the PD substantia nigra for both early-stage (C3d and C4d) and late-stage (C7 and C9) complement proteins, and C3d and C4d staining on Lewy bodies was subsequently reported in the brain stem from subjects with dementia with Lewy bodies (DLB) [22]
Summary
The long-term use of nonsteroidal anti-inflammatory drugs has been associated, in retrospective studies, with decreased risk for PD, suggesting that inflammation may contribute to development of this disorder. The objective of this study was to determine the extent of complement activation, a major inflammatory mechanism, in PD. Multiple neurotoxic processes have been described in the Parkinson's disease (PD) brain including inflammation, oxidative stress, excitotoxicity, and mitochondrial dysfunction [1]. A third study found no complement reactivity on Lewy bodies in the cingulate gyrus in either PD or DLB [23] Because of these conflicting results, the extent of complement activation in PD is unclear. The objective of the present study was to further examine this issue
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