Published online before print April 6, 2009

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(American Journal of Pathology. 2009;174:1880-1890.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080947

Statin Therapy Inhibits Remyelination in the Central Nervous System

Veronique E. Miron^*, Simone P. Zehntner, Tanja Kuhlmann, Samuel K. Ludwin^¶, Trevor Owens^||, Timothy E. Kennedy, Barry J. Bedell and Jack P. Antel^*

From the Neuroimmunology Unit,^* the Centre for Neuronal Survival, and the Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; the Institute of Neuropathology, University Hospital, Munster, Germany; the Department of Neuropathology,^¶ Queen’s University, Kingston, Ontario, Canada; and the Centre for Medical Biotechnology,|| Institute of Medical Biology, University of Southern Denmark, Denmark

Remyelination of lesions in the central nervous system contributes to neural repair following clinical relapses in multiple sclerosis. Remyelination is initiated by recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating oligodendrocytes. Simvastatin, a blood-brain barrier-permeable statin in multiple sclerosis clinical trials, has been shown to impact the in vitro processes that have been implicated in remyelination. Animals were fed a cuprizone-supplemented diet for 6 weeks to induce localized demyelination in the corpus callosum; subsequent return to normal diet for 3 weeks stimulated remyelination. Simvastatin was injected intraperitoneally during the period of coincident demyelination and OPC maturation (weeks 4 to 6), throughout the entire period of OPC responses (weeks 4 to 9), or during the remyelination-only phase (weeks 7 to 9). Simvastatin treatment (weeks 4 to 6) caused a decrease in myelin load and both Olig2^strong and Nkx2.2^strong OPC numbers. Simvastatin treatment (weeks 4 to 9 and 7 to 9) caused a decrease in myelin load, which was correlated with a reduction in Nkx2.2^strong OPCs and an increase in Olig2^strong cells, suggesting that OPCs were maintained in an immature state (Olig2^strong/Nkx2.2^weak). NogoA+ oligodendrocyte numbers were decreased during all simvastatin treatment regimens. Our findings suggest that simvastatin inhibits central nervous system remyelination by blocking progenitor differentiation, indicating the need to monitor effects of systemic immunotherapies that can access the central nervous system on brain tissue-repair processes.