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1、CNS Drugs 2007; 21 (10): 789-797 LEADING ARTICLE1172-7047/07/0010-0789/$44.95/0 2007 Adis Data Information BV. All rights reserved. The Role of Anti-Inflammatory Agents in Parkinsons Disease Edith G. McGeer and Patrick L. McGeer Kinsmen Laboratory of Neurological Research, University of British Colu
2、mbia, Vancouver, British Columbia, Canada There is ample and increasing evidence, from studies of human pathology,Abstract animal models and tissue culture, that chronic inflammation occurs in the basal ganglia in patients with Parkinsons disease. In such inflammatory states, activat- ed glia can pr
3、oduce large quantities of free radicals and other neurotoxic materi- als. Dopaminergic neurons appear to be particularly vulnerable to these neurotoxins. The anti-inflammatory drugs that are presently in wide use act on peripheral players in the inflammatory process. Many experiments are under way t
4、o find agents that inhibit more potent contributors, such as the activated microglia or terminal complement proteins. Whether such drugs will slow the process of Parkinsons disease or reduce the high risk of dementia in such patients remains to be determined in future work. Parkinsons disease is a n
5、eurodegenerativenamely chronic inflammation, with many diseases of aging, including Alzheimers disease16 and mac-movement disorder in which the principal pathology ular degeneration.17 In this review we will consideris a severe loss of the dopaminergic neurons of the evidence that neuroinflammation
6、plays a role inthe basal ganglia. A small percentage of cases are progressive dopaminergic cell loss, and examinefamilial but most occur sporadically.1 Some of the some suggestions that have been made for anti-familial cases have been attributed to mutations in inflammatory treatment in Parkinsons d
7、isease.the -synuclein gene,1 while others have been at- tributed to parkin,2-4 leucine-rich repeat kinase 2It is important to realise that inflammation in the (LRRK2),5-11 or DNA polymerase .12 However,brain, such as occurs in Parkinsons disease, is silent the aetiology of most cases is unknown, alt
8、houghbecause the brain has no nerve fibres that carry pain recent work indicates that Parkinsons diseasesignals. Moreover, a local immune reaction in the shares a common pathogenetic mechanism, involv-brain does not necessarily involve the peripheral ing aggregation and deposition of misfolded pro-i
9、mmune system, although some infiltration of pe- teins, with other neurodegenerative diseases, such asripheral immune cells into the brain may occur.18-21 Alzheimers disease and Creutzfeldt-Jakob dis-Immune reactions in the brain occur in the absence ease.13-Synuclein has received the most attentiono
10、f antibodies and without significant involvement of in the study of Parkinsons disease,13 but otherT cells.16 Instead, the reaction depends upon the proteins such as LRRK214 and TAR DNA-bindingsynthesis of inflammatory components by local neu- protein15 may also be involved. Parkinsons diseaserons a
11、nd glia, particularly resident phagocytes, also shares a second pathogenetic mechanism,known as microglia. Microglia, inflammatory cy- 790McGeer 21 (10) Inflammation in Parkinsons Disease791 death induced by rotenone25,41 is further support foring such activation could be beneficial in chronic the r
12、ole of superoxide radicals produced by microg-inflammatory states. lia in the pathogenesis of Parkinsons disease. Some Anti-inflammatory activation of microglia may of the reports on rodent models of Parkinsons dis- be initiated by interleukin (IL)-4 or glucocorticoids. ease have implicated microgli
13、al nitric oxide in cell The macrophage/microglia then secrete leukocyte- death,44-46,48 but this is unlikely to be true of Parkin- attracting chemokines, anti-inflammatory cytokines sons disease since human microglia, unlike those in and some extracellular matrix components. Factors rodents, appear
14、to produce very little nitric oxide.49 secreted by alternatively activated macrophages/ There are several reports that treatment with anti- microglia promote cell proliferation, angiogenesis inflammatories inhibits dopaminergic neurotoxicity and extracellular matrix reconstruction, thus pro- in such
15、 animal models.34 moting wound repair. Anti-inflammatory activation It is interesting to note that dopaminergic neurons may be distinguished by the upregulation of CD163 appear particularly vulnerable to the inflammatory (M130), a member of the scavenger receptor cyste- process. Thus, injection of l
16、ipopolysaccharide into ine-rich superfamily, which is expressed by mono- the substantia nigra leads to permanent damage to cytes and macrophages. CD163 expression is sup- dopaminergic neurons,50 while similar doses do not pressed by proinflammatory mediators such as lipo- appear to affect serotonergic or GABAergic neu- polysaccharide, interferon (IFN)-, and tumour rons50,51 or cells in the rat hippocampus.52 necrosis factor (TNF)-, wh
