Paclitaxel (Taxol) attenuates clinical disease in a spontaneously demyelinating transgenic mouse and induces remyelination.
Treatment with paclitaxel by four intraperitoneal injections (20 mg/kg) 1 week apart attenuated clinical signs in a spontaneously demyelinating model, if given with onset of clinical signs. If given at 2 months of age (1 month prior to clinical signs), disease was almost completely prevented The astrogliosis, prominent in our model, was reversed by paditaxel as determined by astrocyte counts and quantitation of GFAP. Electron microscopic examination of affected regions at 2.5 months demonstrated that the myelin was generally normal. By 4 months of age, demyelination was common in the superior cerebellar peduncle, maximal at 6 months, but continued to 8 months. In addition to myelin vacuolation and nude axons, the presence of many thin myelin sheaths suggested remyelination or partial demyelination. Although no evidence of oligodendrocyte loss was seen, nuclear changes were observed. To substantiate that remyelination was occurring, we measured MBP (18.5 kDa), MBP-exon II, Golli-MBP, TP8, Golli-MBP-J37, platelet-derived growth factor alpha (PDGFR alpha) and sonic hedgehog (SHH). Of these TP8, PDGFR alpha and SHH were up-regulated in the untreated transgenic. After paditaxel treatment, MBP-Exon II, TP8, PDGFR alpha and SHH were further up-regulated. We concluded that some of the effects of paditaxel were to stimulate proteins involved in early myelinating events possibly via a signal transduction mechanism.
Moscarello
M A
MA
Department of Structural Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. mam@sickkids.ca
Mak
B
B
Nguyen
T A
TA
Wood
D D
DD
Mastronardi
F
F
Ludwin
S K
SK
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000648:ultrastructure; D015415:Biomarkers; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000648:ultrastructure; D002531:Cerebellum / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D005911:Gliosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007274:Injections, Intraperitoneal; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009103:Multiple Sclerosis; D009185:Myelin Proteins / Q000096:biosynthesis / Q000235:genetics; D018991:Myelin Proteolipid Protein / Q000235:genetics; D009186:Myelin Sheath / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D020721:Nervous System Autoimmune Disease, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009836:Oligodendroglia / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; C047516:Plp1 protein, mouse; D017239:Paclitaxel