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Synergy between paclitaxel plus an exogenous methyl donor in the suppression of murine demyelinating diseasesDepartment of Structural Biology and Biochemistry, The Hospital for Sick Children, Toronto, Ontario, Canada, fabrizio{at}sickkids.ca
Department of Infection, Immunity, Injury and Repair, The Hospital for Sick Children, Toronto, Ontario, Canada
Department of Infection, Immunity, Injury and Repair, The Hospital for Sick Children, Toronto, Ontario, Canada
Department of Structural Biology and Biochemistry, The Hospital for Sick Children, Toronto, Ontario, Canada
Department of Infection, Immunity, Injury and Repair, The Hospital for Sick Children, Toronto, Ontario, Canada
Toronto General Research Institute, University Health Network, 67 College Street, Rm. 424, Toronto, Ontario, Canada
Toronto General Research Institute, University Health Network, 67 College Street, Rm. 424, Toronto, Ontario, Canada
Department of Infection, Immunity, Injury and Repair, The Hospital for Sick Children, Toronto, Ontario, Canada
Department of Structural Biology and Biochemistry, The Hospital for Sick Children, Toronto, Ontario, Canada Progressive demyelination in multiple sclerosis (MS) reflects the negative balance between myelin damage and repair due to physical and molecular barriers, such as astrocytic glial scars, between oligodendrocytes and target neurons. In this paper, we show that combination therapy with paclitaxel (Taxol®) plus the universal methyl-donor, vitamin B12CN (B12CN), dramatically limits progressive demyelination, and enhances remyelination in several independent, immune and nonimmune, in vivo and in vitro model systems. Combination therapy significantly reduced clinical signs of EAE in SJL mice, as well as the spontaneously demyelinating ND4 transgenic mouse. Astrocytosis was normalised in parallel to ultrastructural and biochemical evidence of remyelination. The combination therapy suppressed T cell expansion, reduced IFN-gamma, while enhancing IFN-beta and STAT-1 expression, STAT-1 phosphorylation and methylation of STAT-1 and MBP in the brain. Paclitaxel/B12CN has nearly identical effects to the previously described combination of IFN-beta/ B12CN, whose clinical usefulness is transient because of IFN-neutralising antibodies, not observed (or expected) with the present drug combination. This report provides a mechanistic foundation for the development of a new therapeutic strategy in humans with MS. Multiple Sclerosis 2007; 13: 596-609. http://msj.sagepub.com
Key Words: autoimmunity • demyelinating disorders • interferon • methylation • multiple sclerosis • paclitaxel • vitamin B12CN
This version was published on June
1, 2007 Multiple Sclerosis, Vol. 13, No. 5,
596-609 (2007) This article has been cited by other articles:
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