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Home arrow Environment arrow Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management
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Endothelial Targets in MS Therapy

Interferon-p

Interferon-p family members, especially interferon-p1b (Betaseron), exhibit multiple mechanistic effects that protect the endothelium in MS. Interferon-p1b decreases the transendothelial migration of monocytes by inhibiting complex formation between monocytes and EMPs [70]. An MS clinical trial has shown decreased T1-weighted gadolinium-enhanced brain lesions and decreased serum MMP-9 by using interferon-p1a plus doxycycline, an anti-inflammatory broad- spectrum MMP inhibitor, combination therapy. Additionally, MS serum induces leukocyte extravasation in vitro. Taken together, this suggests that MMPs play an important role in MS pathophysiology. We reported an elevated level of MMP-8

and MMP-9 in RRMS serum [72], and others have similarly reported elevated levels of MMP-9 in RRMS, PPMS, and SPMS [73]. However, reports of elevated MMP-2 levels in PPMS and SPMS and MMP-9 polymorphisms showed no correlation with disability [73]. Although neutrophils are not commonly believed to contribute to MS pathology, some phases may be mediated at least in part by neutrophils [74]. MMP-8 is associated with neutrophils [75], and CXCR2+ neutrophils may contribute to the oligodendrocyte pathology seen in the cuprizone MS model. Neutrophils from MS patients display an “active” phenotype, which is typically characterized by reduced apoptosis and increased tissue persistence; increased levels of toll-like receptor-2 (TLR-2), formyl peptide receptor (fMLP receptor), interleukin-8 receptor (IL-8R), and cluster of differentiation 43 (CD43); as well as increased granule and superoxide release [76, 77] making them more longer-lasting cellular mediators of inflammation. Occludin is susceptible to proteolysis by MMPs [78, 79], which degrade and disintegrate TJ architecture required for BBB function. Cytokines such as TNF-a and IL-1-p are known to induce MMP synthesis in several cell types within the BBB [80]. Additionally hypoxia, which contributes to MS and Alzheimer’s pathogenesis, can activate pro-forms of MMP to active enzymes which can degrade occludin in TJs [81]. Therefore, MMP activity represents a potential therapeutic target for interferon-p in MS treatment. MMPs also directly target and degrade interferon-p. The use of minocycline, a potent MMP inhibitor, has anti-inflammatory effects that help to maintain interferon-p at therapeutic levels [82].

 
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