Statin therapy inhibits remyelination in the central nervous system.
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.
Neuroimmunology Unit, the Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Veronique E
VE
Miron
Simone P
SP
Zehntner
Tanja
T
Kuhlmann
Samuel K
SK
Ludwin
Trevor
T
Owens
Timothy E
TE
Kennedy
Barry J
BJ
Bedell
Jack P
JP
Antel
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000008:administration & dosage; D003471:Cuprizone / Q000008:administration & dosage; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000502:physiology; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D009416:Nerve Regeneration / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology*; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology; D029961:Zebrafish Proteins
D000924:Anticholesteremic Agents; D051792:Basic Helix-Loop-Helix Proteins; D002614:Chelating Agents; D003471:Cuprizone; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D012333:RNA, Messenger; D019821:Simvastatin; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715627:Nkx2-2 protein, mouse; C512773:Olig2 protein, mouse; C000715630:nkx2.2b protein, zebrafish