Synergy between paclitaxel plus an exogenous methyl donor in the suppression of murine demyelinating diseases.
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.
Mastronardi
F G
FG
Department of Structural Biology and Biochemistry, The Hospital for Sick Children, University Health Network, Toronto, Ontario, Canada. fabrizio@sickkids.ca
Tsui
H
H
Winer
S
S
Wood
D D
DD
Selvanantham
T
T
Galligan
C
C
Fish
E N
EN
Dosch
H-M
HM
Moscarello
M A
MA
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000473:pathology; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000473:pathology; D004357:Drug Synergism; D005911:Gliosis / Q000188:drug therapy / Q000473:pathology; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009416:Nerve Regeneration / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D014805:Vitamin B 12 / Q000494:pharmacology*; D014803:Vitamin B Complex / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D004676:Myelin Basic Protein; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014803:Vitamin B Complex; D014805:Vitamin B 12; D017239:Paclitaxel