Synergy between paclitaxel plus an exogenous methyl donor in the suppression of murine demyelinating diseases
| Autor: | Winer S, Mastronardi Fg, Dosch Hm, Carole L. Galligan, Tsui H, Mario A. Moscarello, Eleanor N. Fish, D. D. Wood, Selvanantham T |
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| Rok vydání: | 2007 |
| Předmět: |
Genetically modified mouse
Combination therapy Paclitaxel T-Lymphocytes Mice Inbred Strains Mice Transgenic Methylation Nerve Fibers Myelinated Autoimmune Diseases Myelin Mice medicine Animals Gliosis Remyelination Demyelinating Disorder business.industry Multiple sclerosis Drug Synergism Myelin Basic Protein medicine.disease Antineoplastic Agents Phytogenic Oligodendrocyte Nerve Regeneration Vitamin B 12 medicine.anatomical_structure STAT1 Transcription Factor Neurology Immunology Vitamin B Complex Cancer research Neuroglia Neurology (clinical) business Demyelinating Diseases |
| Zdroj: | Multiple sclerosis (Houndmills, Basingstoke, England). 13(5) |
| ISSN: | 1352-4585 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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