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Health search cidpusa NeuropathyN-acetyl-L-cysteine ameliorates the inflammatory disease process in experimental autoimmune encephalomyelitis in Lewis rats Romesh Stanislaus,Anne G Gil Avtar K Singh and Inderjit Singh 1Department of Biostatistics, Bioinformatics & Epidemiology, Medical University of South Carolina, Charleston, SC, USA 2Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA Journal of Autoimmune Diseases 2005, 2:4 doi:10.1186/1740-2557-2-4 Keywords: EAE, Macrophages, infiltration N-acetyl-L-cysteine, CNS We report that N-acetyl-L-cysteine (NAC) treatment blocked induction of TNF-a, IL-1ß, IFN-? and iNOS in the CNS and attenuated clinical disease in the myelin basic protein induced model of experimental allergic encephalomyelitis (EAE) in Lewis rats. Infiltration of mononuclear cells into the CNS and induction of inflammatory cytokines and iNOS in multiple sclerosis (MS) and EAE have been implicated in subsequent disease progression and pathogenesis. To understand the mechanism of efficacy of NAC against EAE, we examined its effect on the production of cytokines and the infiltration of inflammatory cells into the CNS. NAC treatment attenuated the transmigration of mononuclear cells thereby lessening the neuroinflammatory disease. Splenocytes from NAC-treated EAE animals showed reduced IFN-? production, a Th1 cytokine and increased IL-10 production, an anti-inflammatory cytokine. Further, splenocytes from NAC-treated EAE animals also showed decreased nitrite production when stimulated in vitro by LPS. These observations indicate that NAC treatment may be of therapeutic value in MS against the inflammatory disease process associated with the infiltration of activated mononuclear cells into the CNS. Outline 1. Introduction Multiple sclerosis (MS) is a chronic demyelinating disease marked by focal destruction of myelin, resulting in the loss of oligodendrocytes and axons accompanied by an inflammatory disease process [1-3]. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS. Both MS and EAE are initiated by a T-cell mediated autoimmune response (CD4+ and CD8+) against myelin components followed by induction of inflammatory mediators (chemokines and cytokines) that in turn define the pattern of perivascular migration of activated T-cells and mononuclear cells into the CNS [1-4]. The brain is particularly vulnerable to oxidative stress due to its high consumption of oxygen and glucose, enrichment in unsaturated fatty acids that are subject to oxidation, and presence of regions enriched in iron and ascorbate that are potent pro-oxidants for brain membranes. Moreover, higher levels of glucose upregulate the neuroinflammatory process measured as induction of iNOS and NO production [38]. Coupled with the relatively reduced antioxidant defenses in the brain, exposure of brain cells to reactive oxygen or nitrogen species can be detrimental and is thought to contribute to the pathogenesis of many brain disorders [39]. Oxidative stress is important in the etiology of EAE and is thought to contribute directly to CNS damage [7,40]. N-acetyl-L-cysteine (NAC) as cysteine, a precursor of glutathione, is a potent anti-oxidant. By scavenging superoxide radicals, metallothionein and other antioxidants such as cysteine, N-acetyl-cysteine and glutathione offer neuroprotection [41]. In vivo NAC enhances hippocampal neuronal survival after transient forebrain ischemia in rats [42]. Partial protection of neurons from the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was achieved by four different antioxidants including NAC in the mouse [43]. NAC also has a protective effect in pneumococcal meningitis in the rat [44]. In vitro, NAC promotes oligodendrocyte survival in the presence of toxic stimuli or due to withdrawal of growth factors [45] and maturation of oligodendrocytes [46]. NAC inhibits Theiler's virus-induced NO and TNF-a production by murine SJL/J astrocyte cultures [47]. NAC treatment prevented cytokine-induced decrease in GSH and degradation of sphingomyelin to ceramide, also blocked cytokine-mediated ceramide production in rat primary oligodendrocytes, microglia, and C6 glial cells, thereby preventing cell death. These results suggest that intracellular levels of GSH may play a critical role in the regulation of cytokine-induced generation of ceramide leading to apoptosis of brain cells in demyelinating diseases. [48] In summary, the ability of NAC to inhibit the induction of proinflammatory cytokines and inhibit the transmigration of inflammatory cells into the CNS of EAE-induced rats identifies it as a potential drug for the treatment of neuroinflammatory diseases and possibly other Th1-mediated autoimmune diseases. In addition, in vitro studies suggest that NAC may also promote survival of neurons and oligodendrocytes and thereby potentially facilitating remyelination. MS is a multifactorial disease and the etiology of the disease in unknown. Consequently, the targets for the prevention of the disease are currently unknown. However the disease signs and causes of these are known. For example an increase in pro-inflammatory cytokines and iNOS activity has been linked increase in clinical sign. As evidenced in the manuscript, NAC can inhibit the production of inflammatory cytokines and nitrotyrosine in the CNS during EAE pathogenesis. Thus, NAC holds out to be a promising therapeutic agent for the amelioration of MS/EAE. ----------------------------------------------------------------------- all natural remedies diet guide and spiritual healing see services link | |
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