Multiple sclerosis pathophysiology

Chemokines have been shown to be associated with a number of autoinflammatory diseases including multiple sclerosis, rheumatoid arthritis, atherosclerosis, dermatitis, and organ transplant rejection. Evidence, reviewed below, is mounting that chemokines may play a major role in the pathophysiology of these diseases and thus chemokine receptor antagonists could prove to be useful therapeutics in treating these and other proinflammatory diseases. 

Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for ARF is renal vascular vasoconstriction.41 It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy with other nephrotoxic drugs.41 Cyclosporine and tacrolimus are extensively metabolized by... 

Bainbridge JL, CorboyJR, Gidal BE. Multiple sclerosis. In DiPiroJT, et al, eds. Pharmacotherapy A Pathophysiologic Approach. 5th ed. New York McGraw-Hill 2002. 

Because of the instability of peroxynitrite under physiological conditions, the detection of 3-nitrotyrosine (NC>2-Tyr) has become a biochemical marker for the presence of peroxynitrite in pathophysiological processes. The biological significance of tyrosine nitration is a subject of great interest, because extensive evidence supports the formation of nitrotyrosine in vivo in diverse pathological conditions such as heart diseases, chronic inflammation and autoimmune diseases, cancer, Parkinson s disease, Alzheimer s disease, multiple sclerosis, amyotrophic lateral sclerosis, and ischemia-reperfusion injury [11]. 

An inconvenient but more descriptive name for this MS is intermittent, patchy demyelination. This clumsy term makes clear that multiple sclerosis is unlikely to be a single entity in terms of cause (etiology) or disease mechanisms (pathophysiology). In principle, any conditions or combination of conditions that lead to intermittent, patchy demyelination are forms of multiple sclerosis. If a clear cause can be identified, the condition is by convention not referred to as multiple sclerosis. The disease is therefore by definition of unclear etiology. The neurology literature of the last 100 years contains confident declarations that multiple sclerosis has been proven to be a viral disease, that it has been proven not to be a viral disease, that it has been proven to be an immune disease, that immune mechanisms in multiple sclerosis have been shown to be secondary to the disease process, and so on. 

Death of OL and subsequent myelin loss has been reported in a variety of myelin disorders including, multiple sclerosis (MS), X-adrenoleukodystrophy (X-ALD), adrenomyeloneu-ropathy (AMN), vascular dementia, periventricular leukomalacia (PVL), hypoxia, and ischemia. Several factors that might be associated with OL death in these pathophysiological concU-dons are discussed below. 

Smith KJ, McDorrald WI (1999) The pathophysiology of multiple sclerosis The mechanism urrderlyirrg the productiorr of symptoms arrd the rratural history of the disease. Philos Trarrs R Soc Lorrd B Biol Sci 354 1649-1673. 

McDonald I (1998) Pathophysiology of multiple sclerosis. In McAl-pines Multiple Sclerosis (Compston A, Ebers G, Lassmann H, McDonald I, Matthews B, Wekerle H, eds), pp 359-378. London Harcout Brace and Co. Ltd. 

Not surprisingly, disturbance in the KP has been implicated in a number of diseases, and pharmacological intervention has thus potential for treatment. The immunosuppressive effects of the KP metabolites in the periphery are used in the treatment of multiple sclerosis (MS), where synthetic kynurenines are undergoing clinical development. Furthermore, IDO inhibitors are in preclinical development to treat cancers, for example, ovarian and colorectal [34]. This has been reviewed extensively elsewhere [3, 35], and the focus of the discussion in this review will be on the role of KP metabolites in brain pathophysiology. 

Hemcion RM. Multiple Sclerosis Immunology, Patiiology, and Pathophysiology. New York Demos Medical Publishing, 2003. 

CCRl plays an important role in host defense and is involved in regulating the chemotaxis of immune cells, a feature it shares in common with all chemoldne receptors. Dysregulation of this response leads to autoimmunity and CCRl has been associated with the pathophysiology of a number of diseases including rheumatoid arthritis [7-9], multiple sclerosis [10-12], transplant rejection [13, 14] and allergic inflammation [15-17]. 

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