A novel calpain inhibitor for the treatment of acute experimental autoimmune encephalomyelitis

Hassen, Getaw Worku; Feliberti, Jason; Kesner, Leo; Stracher, Alfred; Mokhtarian, Foroozan

doi:10.1016/j.jneuroim.2006.08.005

Cited by 31 publications

(41 citation statements)

References 61 publications

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“…The striking characteristics of CYLA to cross the BBB, permeate cell membranes, making it available to the central nervous system (CNS) are essential for enhancing the uptake of the drug in the CNS and for reducing calpain activity. The effect of CYLA in suppressing inflammation and demyelination in acute EAE was reported in our previous work (Hassen et al, 2006). …”

Section: Introductionsupporting

confidence: 63%

“…The experimental methods used were similar to those described in our earlier publication (Hassen et al, 2006). EAE was induced by injecting each mouse subcutaneously (s.c.) in each flank with a 100μl of an emulsion containing incomplete Freund’s adjuvant (IFA) supplemented with 500μg heat inactivated mycobacterium tuberculosis (Sigma St. Louis, MO, ) and 300μg MOG 35–55.…”

Section: Methodsmentioning

confidence: 99%

“…Experimental autoimmune encephalomyelitis, an animal model of MS, has been extensively used to study the pathogenesis of MS (Mokhtarian et al, 1984; Mokhtarian and Swoveland, 1987; Ofosu-Appiah et al, 1994; Mokhtarian et al, 1996; Mokhtarian et al, 1999) as well as treatment options (Mokhtarian et al, 1996; Gilgun-Sherki et al, 2003a; Gilgun-Sherki et al, 2003b; Bechtold et al, 2004; Hassen et al, 2006). Inflammation that leads to the production of nitric oxide (NO), tumor necrosis factor (TNF)-alpha and proteases, including calpain, contributes to the destruction of myelin and eventually causes injury to the axons (Banati et al, 1993; Lannes-Vieira et al, 1994; Gehrmann et al, 1995; Benveniste, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Prevention of axonal injury using calpain inhibitor in chronic progressive experimental autoimmune encephalomyelitis

et al. 2008

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Axonal injury is the major correlate of permanent disability in neurodegenerative diseases such as multiple sclerosis (MS), especially in secondary-progressive MS following relapsing-remitting disease course. Proteolytic enzyme, calpain, is a potential candidate for causing axonal injury. Most current treatment options only target the inflammatory component of MS. Previous work using calpain inhibitor CYLA in our laboratory showed significant reduction in clinical sign, demyelination and tissue calpain content in acute experimental autoimmune encephalomyelitis (EAE). Here we evaluated markers of axonal injury (amyloid precursor protein, Nav1.6 channels), neuronal calpain content and the effect of CYLA on axonal protection using histological methods in chronic EAE [myelin oligodendrocyte glycoprotein (MOG) – induced disease model of MS]. Intraperitoneal application of CYLA (2mg/mouse/day) significantly reduced the clinical signs, tissue calpain content, demyelination and inflammatory infiltration of EAE. Similarly, markers for axonal injury were barely detectable in the treated mice. Thus, this novel drug, which markedly suppresses the disease course, axonal injury and its progression, is a candidate for the treatment of a neurodegenerative disease such as multiple sclerosis.

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Section: Introductionsupporting

confidence: 63%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prevention of axonal injury using calpain inhibitor in chronic progressive experimental autoimmune encephalomyelitis

et al. 2008

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“…Increased activity and expression of calpain have been detected in CNS tissue, immune cells of MS patients and in its corresponding animal model, EAE [187,188,189]. During the active stage of MS pro-inflammatory Th1/Th17 cells predominate over immuno-regulatory Th2/Treg cells [190].…”

Section: Cytokine-based Immuno-interventionmentioning

confidence: 99%

Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination

et al. 2013

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Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8+, NKT, CD4+CD25+ T regulatory cells) and B cells are involved in this disorder, thus new MS therapies seek damage prevention by resetting multiple components of the immune system. The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective. This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination—with emphasis upon myelin composition/architecture and oligodendrocyte maturation and differentiation. The translational options target oligodendrocyte protection and myelin repair in animal models and assess their relevance in human. Remyelination may be enhanced by signals that promote myelin formation and repair. The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination.

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“…Proteases (acidic and neutral) that degrade these proteins and cytoskeletal proteins have been implicated in myelinolysis and cell death Shields and Banik, 1998b). Increased activity and expression of the Ca 2+ -activated protease calpain has been found in tissue of patients with MS as well as in the corresponding animal model, experimental allergic encephalomyelitis (EAE) (Banik, 1992;Cuzner et al, 1975;Guyton et al, 2005;Hassen et al, 2006;Shields and Banik, 1998a;Shields et al, 1998;Smith, 1977).…”

Section: Introductionmentioning

confidence: 99%

Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients

Imam

Guyton

Haque

et al. 2007

Journal of Neuroimmunology

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Multiple sclerosis (MS) is a devastating autoimmune demyelinating disease of the CNS. This study investigated whether expression and activity of the calcium-activated protease calpain correlated with Th1/Th2 dysregulation in MS patients during states of relapse and remission. Calpain expression and activity were significantly increased in peripheral blood mononuclear cells (PBMCs) from MS patients, compared to controls, with the highest expression and activity noted during relapse. Th1 cytokines were highest and Th2 cytokines were lowest in MS patients during relapse. Treatment with calpain inhibitor, calpeptin, decreased Th1 cytokines in PBMCs from MS patients. Calpain inhibitor also reduced degradation of myelin basic protein (MBP) by inhibiting the calpain secreted from MBPspecific T cells. Taken together, these results suggested calpain involvement in Th1/Th2 dysregulation in MS patients.

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A novel calpain inhibitor for the treatment of acute experimental autoimmune encephalomyelitis

Cited by 31 publications

References 61 publications

Prevention of axonal injury using calpain inhibitor in chronic progressive experimental autoimmune encephalomyelitis

Prevention of axonal injury using calpain inhibitor in chronic progressive experimental autoimmune encephalomyelitis

Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination

Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients

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