Cytokines demyelination

Like spinal cord trauma, traumatic head injury consists of a primary injury, attributable to the mechanical insult itself, and a secondary injury, attributable to the series of systemic and local neurochemical changes that occur in brain after the initial traumatic insult (Klussmann and Martin-Villalba, 2005). The primary injury causes a rapid deformation of brain tissues, leading to rupture of neural cell membranes, release of intracellular contents, and disruption of blood flow and breakdown of the blood-brain barrier. In contrast, secondary injury to the brain tissue includes many neurochemical alterations such as release of cytokines, glial cell reactions involving both activated microglia and astroglia, and demyelination... 

Chabas D, Baranzini SE, Mitchell D, Bernard CC, Riffling SR, Denhardt DT, et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 2001 294(5547) 1731-1735. 

In addition to the effect of increased VLCFA on membrane and possibly cellular function, the rapid cerebral form of X-ALD is characterized by an inflammatory response that is believed to contribute to the demyelination that characterizes this phenotype and which is similar to that seen in multiple sclerosis. These cerebral lesions are characterized by breakdown in myelin with sparing of the axons accompanied by the accumulation of cholesterol ester in the neurons. A perivascular inflammatory response with infiltration of T cells, B cells, and macrophages also is present. Therefore, it is believed that the rapid cerebral disease has an im-munologically-mediated component. It has been suggested that the inflammatory response occurs in response to the elevated levels of VLCFA in lipids, which elicits an inflammatory cascade that may be mediated in part by cytokines. Once this cascade begins, it may be more difficult to intervene in the disease process, and in general therapeutic interventions studied to date have been most effective when initiated early. Therefore, prevention of the initiation of the immune response is important for improving outcome. 

Singh I, Pahan K, Khan M, Singh AK (1998) Cytokine-mediated ceramide production is redox sensitive Implications to proinflam-matory cytokine-mediated apoptosis in demyelinating diseases. J Biol Chem 273 20354-20362. 

Linker RA, Maurer M, Gaupp S, Martini R, Holtmann B, Giess R, Rieck-mann P, Lassmann H, Toyka KV, Sendtner M, Gold R (2002) CNTE is a major protective factor in demyelinating CNS disease A neurotrophic cytokine as modulator in neuroinflammation. Nat Med 8 620-624. 

An upregulation of ICAM-1 and VCAM-1 on the surface of endothelial cells is generally attributed to the activity of inflammatory cytokines such as TNF-a, IL-1, IL-4, and IFN-y.43-83-86 All of these cytokines are readily identifiable in the CNS lesions of MS,87-90 particularly in close proximity to blood vessel walls.82-91 In EAE, disease activity is exacerbated by TNF-a,92-93 antagonised by specific neutralising antibodies,94 and injection of TNF-a into rat spinal cord induces mononuclear cell infiltrates.95 However, several of the cytokines identified in MS lesions are also present in the CNS of normal and noninflammatory disease controls91 and therefore caution must be applied in interpreting cytokine expression and localisation to a particular phase of demyelination. 

MS is an inflammatory demyelinating autoimmune disease affecting the CNS. In MS, the immune system attacks the myelin sheath of nerve cell fibers in the brain and spinal cord. MS is predominantly a T-lymphocyte mediated disorder, and cytokines may therefore have a key role in the pathogenesis of the disease. MS is the only neurological disorder where therapeutic manipulation of the cytokine system influences development of the disease (Adibhatla and Hatcher,... 

WIN55212-2 5-20 mg/kg Mouse, TMEV-induced demyelinating disease T-cell proliferation, antiviral THl- and TH2-type cytokines... 

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