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Statin Therapy Inhibits Remyelination in the Central Nervous System

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

Abstract

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 Olig2strong and Nkx2.2strong 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 Nkx2.2strong OPCs and an increase in Olig2strong cells, suggesting that OPCs were maintained in an immature state (Olig2strong/Nkx2.2weak). 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

Topics: Regular Articles
Publisher: American Society for Investigative Pathology
OAI identifier: oai:pubmedcentral.nih.gov:2671276
Provided by: PubMed Central
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