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Paclitaxel (Taxol) attenuates clinical disease in a spontaneously demyelinating transgenic mouse and induces remyelination

Departments of Structural Biology and Biochemistry, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8, mam{at}sickkids.ca

B Mak

Department of Surgery, University of Washington, Seattle, Washington, USA

T A Nguyen

Departments of Structural Biology and Biochemistry, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8

D D Wood

Departments of Structural Biology and Biochemistry, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8

F Mastronardi

Departments of Structural Biology and Biochemistry, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8

S K Ludwin

Department of Pathology, Queen's University and Kingston General Hospital, Kingston, Ontario, Canada

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 paclitaxel 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 a (PDGFRa) and sonic hedgehog (SHH). Of these TP8, PDGFRa and SHH were up-regulated in the untreated transgenic. After paclitaxel treatment, MBP-Exon II, TP8, PDGFRa and SHH were further up-regulated. We concluded that some of the effects of paclitaxel were to stimulate proteins involved in early myelinating events possibly via a signal transduction mechanism.

Key Words: demyelination • DM20 • multiple sclerosis • paclitaxel • remyelination

Multiple Sclerosis, Vol. 8, No. 2, 130-138 (2002)
DOI: 10.1191/1352458502ms776oa


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