Brain Advance Access originally published online on May 18, 2008
Brain 2008 131(6):1464-1477; doi:10.1093/brain/awn080
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Remyelination protects axons from demyelination-associated axon degeneration
Department of Veterinary Medicine, MS Society Cambridge Centre for Myelin Repair, Madingley Road, Cambridge, CB3 OES, UK
Correspondence to: K.-A. Irvine, PhD, Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, 1001 Potrero Avenue, Building 1, Rm 101, University of California, San Francisco, CA 94110, USA E-mail: karen.irvine{at}ucsf.edu
In multiple sclerosis, demyelination of the CNS axons is associated with axonal injury and degeneration, which is now accepted as the major cause of neurological disability in the disease. Although the kinetics and the extent of axonal damage have been described in detail, the mechanisms by which it occurs are as yet unclear; one suggestion is failure of remyelination. The goal of this study was to test the hypothesis that failure of prompt remyelination contributes to axonal degeneration following demyelination. Remyelination was inhibited by exposing the brain to 40 Gy of X-irradiation prior to cuprizone intoxication and this resulted in a significant increase in the extent of axonal degeneration and loss compared to non-irradiated cuprizone-fed mice. To exclude the possibility that this increase was a consequence of the X-irradiation and to highlight the significance of remyelination, we restored remyelinating capacity to the X-irradiated mouse brain by transplanting of GFP-expressing embryo-derived neural progenitors. Restoring the remyelinating capacity in these mice resulted in a significant increase in axon survival compared to non-transplanted, X-irradiated cuprizone-intoxicated mice. Our results support the concept that prompt remyelination protects axons from demyelination-associated axonal loss and that remyelination failure contributes to the axon loss that occurs in multiple sclerosis.
Key Words: ageing; axonal degeneration; oligodendrocyte progenitor cells; multiple sclerosis; remyelination; stem cells
Abbreviations:
CR, callosal radiation; MCC, medial corpus callosum; TNF-
, tumour necrosis factor .
Received November 30, 2007. Revised March 26, 2008. Accepted April 2, 2008.
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