The inflammatory response in the Parkinson brain
Introduction
Parkinson's disease (PD) is the second most frequent neurodegenerative disorder in the elderly. Although many efforts have been made to unravel the origin of PD, its etiology still remains a mystery thus challenging us in preventing the disease to occur. Moreover, despite the existence of efficient treatments that alleviate most of the disabling symptoms, their chronic use is most often associated with adverse side effects. It is therefore of great importance to develop new therapeutic strategies aimed at slowing or even halting the degenerative processes. The design of such neuroprotective therapies is curbed however by our limited knowledge of the mechanism by which the dopaminergic neurons degenerate in PD. In the past few years, tremendous progress has been achieved in our understanding of the pathogenesis of PD. Thanks to postmortem studies, and more recently to animal models of the disease, significant insight and clues have been provided into the mechanism by which dopaminergic neurons degenerate in this pathology. To date, it is well accepted that increased oxidative stress is likely to play a prominent role in the degenerative process [1]. Other hypotheses have also been postulated including altered calcium homeostasis, growth factor deficiency, and excitotoxic mechanisms [2], [3]. Nonetheless, it is difficult to reconcile most of these biochemical alterations in a temporal context and thus to firmly determine if they are instrumental in the cell death process or if they just represent a pathological consequence. Because of the progressive nature of the disease, one may speculate that once the neurodegenerative process has been initiated by the etiological factor(s), a cascade of secondary deleterious events is set in motion and account for those biochemical alterations observed in the brain of parkinsonian patients. Such a hypothesis is supported by recent findings showing evidence of an on-going neuronal degeneration, as demonstrated by the presence of numerous active microglial cells, in the substantia nigra of drug addicts intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) several decades after a short-time period exposure to the neurotoxin [4]. In this context, another tantalizing hypothesis is the possibility that a subset of reactive glial cells may participate to dopaminergic cell demise during PD. Almost invariably observed in all neurodegenerative disorders, the glial reaction is generally considered simply as a consequence of neuronal cell death. However accumulating evidence suggests that reactive glial cells by virtue of their inflammatory properties may play a significant role in the cascade of events leading to and sustaining nerve cell death in PD. This review summarizes these findings and discusses the potential involvement of inflammation in the mechanism of nerve cell death in PD.
Section snippets
Has Parkinson's disease an immune-based origin?
The term ‘inflammation’ is generally used to describe local accumulation of fluid, plasma proteins and white blood cells that is initiated by physical injury, infection or a local immune response. While acute inflammatory response denotes an early and often transient episode, chronic inflammation occurs when the infection persists or during an autoimmune response. In the later case, the effector pathways of immunity most often cause chronic inflammatory injury to tissues, which may prove
The inflammatory reaction in the brain of parkinsonian patients
Several lines of evidence support the existence of inflammatory-related mechanisms in the brain of patients with Parkinson's disease. First, many investigators have reported a marked increase of cytokine levels in the striatum and CSF of parkinsonian patients compared to control subjects. Those include pro-inflammatory cytokines (TNF-α, IL-1β, Il-6), T-cell activation-associated cytokine (IL-2), anti-inflammatory cytokine (IL-4) and several growth factors (EGF, TGF-α, bFGF, TGF-β1) (for review
Does inflammation play a role in PD pathogenesis?
Because chronic inflammation can have devastating consequences on the cellular environment, it is tempting to speculate that the inflammatory processes observed in PD may play some role in the pathogenesis. However, this issue can be hardly addressed by postmortem studies. In fact, much insight on the potential involvement of inflammation-mediated nerve cell death in PD came from studies in animal model of the disease. Indeed, it has been shown that intranigral injection of the immunostimulant
Mechanisms of inflammation-mediated cytotoxicity in PD
Recently, many research efforts have been focused on the molecular mechanisms by which inflammatory processes may induce neurotoxicity. It is widely assumed that pro-inflammatory cytokines trigger most of these toxic events although other pathways such as activation of the complement system may also be important [60].
Concluding remarks
From the many studies summarized above it has become clear that inflammatory processes in PD represent an important pathological feature of the disease. Elevated cytokines, MHC antigen and inflammatoty-associated molecules (iNOS, COX-2) expression has been systematically observed both in parkinsonian patients and in several animal models of the disease. Although it is now generally accepted that inflammatory events are likely to play an important role into the pathogenesis of PD, many questions
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The first two authors contributed equally to this work.