Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

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Collins, Louise M.
Toulouse, André
Connor, Thomas J.
Nolan, Yvonne M.
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Idiopathic Parkinson’s disease (PD) represents a complex interaction between the inherent vulnerability of the nigrostriatal dopaminergic system, a possible genetic predisposition, and exposure to environmental toxins including inflammatory triggers. Evidence now suggests that chronic neuroinflammation is consistently associated with the pathophysiology of PD. Activation of microglia and increased levels of pro-inflammatory mediators such as TNF-alpha,IL-1beta and IL-6, reactive oxygen species and eicosanoids has been reported after post mortem analysis of the substantia nigra from PD patients and in animal models of PD. It is hypothesised that chronically activated microglia secrete high levels of pro-inflammatory mediators which damage neurons and further activate microglia, resulting in a feed forward cycle promoting further inflammation and neurodegeneration. Moreover, nigrostriatal dopaminergic neurons are more vulnerable to pro-inflammatory and oxidative mediators than other cell types because of their low intracellular glutathione concentration. Systemic inflammation has also been suggested to contribute to neurodegeneration in PD, as lymphocyte infiltration has been observed in brains of PD patients and in animal models of PD, substantiating the current theory of a fundamental role of inflammation in neurodegeneration. We will examine the current evidence in the literature which offers insight into the premise that both central and systemic inflammation may contribute to neurodegeneration in PD. We will discuss the emerging possibility of the use of diagnostic tools such as imaging technologies for PD patients. Finally, we will present the immunomodulatory therapeutic strategies that are now under investigation and in clinical trials as potential neuroprotective drugs for PD.
Parkinson's disease , Neuroinflammation , Systemic inflammation , Microglia , Cytokines , Immunomodulatory therapies
Collins L.M., Toulouse A., Connor T.J., Nolan Y.M. (2012) 'Contributions of central and systemic inflammationto the pathophysiology of Parkinson's disease'. Neuropharmacology, 62(7), pp. 2154–2168.
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Copyright © 2012, Elsevier. NOTICE: this is the author’s version of a work that was accepted for publication in Neuropharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neuropharmacology, [62, June 2012]