Review
Inflammation and neurodegeneration in Parkinson's disease

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Abstract

The immunohistochemical demonstration of reactive microglia and activated complement components suggests that chronic inflammation occurs in affected brain regions in Parkinson's disease (PD). Evidence from humans and monkeys exposed to MPTP indicates this inflammation may persist many years after the initial stimulus has disappeared. Chronic inflammation can damage host cells. Reports in the literature indicate that antiinflammatory agents inhibit dopaminergic cell death in animal models of PD, and there is one epidemiological report that their use significantly diminishes the risk of PD in humans. There is a marked elevation in the mRNA levels for complement proteins and markers of activated microglia in affected regions in PD. The upregulation appears greater than that found in inflamed arthritic joints. These data support the hypothesis that chronic inflammation may play an important role, if secondary, in the pathogenesis of PD.

Introduction

Immunohistochemical and molecular biological evidence accumulated over the past two decades has shown that the brain is capable of sustaining an innate immune response and that the result may be damaging to host cells. The evidence for a chronic inflammatory reaction in the brain is particularly strong in Alzheimer's disease (AD) where it has been extensively studied [1], but there is also a considerable literature suggesting that a local immune reaction occurs in affected regions of the brain in Parkinson's disease (PD). The large number of recent reviews on the subject bears witness to the growing realization of the possible importance of this inflammatory response to PD progression [2], [3], [4], [5], [6], [7], a hypothesis receiving strong support from the recent epidemiological report that chronic use of nonsteroidal antiinflammatory drugs reduces significantly the risk of PD by about 45% [8].

Inflammation in the brain is silent because the brain has no pain fibers. Moreover, a local brain immune reaction does not involve the peripheral immune system. It occurs without antibodies and without significant involvement of T cells. Instead, the reaction depends upon the synthesis of inflammatory components by local neurons and glia, and especially resident phagocytes—which, in the brain, are the microglia. Microglia, inflammatory cytokines and the complement system appear to play significant roles.

Section snippets

Microglia

Microglia constitute about 10% of all glia. They are generally in the resting state in normal adult brain. When activated, they upregulate a variety of receptors and other molecules involved in inflammation and phagocytosis. In the activated state, they may also produce large amounts of superoxide anions and other potential neurotoxins. In culture, microglia have been shown to contribute to neurotoxic processes, including attack on dopaminergic cells [9], [10], [11], [12], [13]. A profusion of

Cytokines

Inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), interleukin-1 (IL-1) and IL-6, amplify and sustain inflammation and immune responses. In the periphery, they are thought to be primarily responsible for many of the clinical and pathological manifestations of such diseases as rheumatoid arthritis and inflammatory bowel syndrome. It is of some interest, therefore, that increased levels of IL-1b, IL-6 and TNFα have been found in the basal ganglia and CSF of PD patients [2]. The

The complement system

Complement is a phylogenetically primitive system, considerably predating the adaptive immune system, which developed later in vertebrates. It is thus not surprising that the system can be activated by molecules other than antibodies. One such molecule, which is found elevated in the SN in PD, is C-reactive protein (Fig. 2). Once activated, the complement cascade (Fig. 3) produces anaphylatoxins which promote further inflammation, opsonizing components which mark material for phagocytosis and

Conclusions

The evidence that a chronic inflammatory reaction may be contributing to neuronal death is certainly not as strong in PD as it is in AD, where there are many epidemiological data and one small pilot trial [1] to support the hypothesis that antiinflammatory agents might delay the onset and slow the progression of the disease. Nevertheless, it seems possible that treatment with antiinflammatory agents might slow the progress of dopaminergic cell death in PD, and this is in accord with the one

Acknowledgements

Work on PD was supported by grants from the Pacific Parkinson's Research Institute, the Parkinson Society Canada and the MRC of Canada, as well as donations from the Jack Brown and Family Foundation and Mr Guy Mills.

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