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 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.
Highlights
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,ʈ Institute of Medical Biology, University of Southern Denmark, Denmark
We report that simvastatin significantly inhibits the robust remyelination that normally occurs subsequent to central nervous system (CNS) demyelination from oral administration of the oligodendrocyte toxin, cuprizone
When assessing myelin levels in the corpus callosum, there was no significant difference between animals treated with cuprizone alone and those treated with cuprizone and the vehicle used to reconstitute the simvastatin, demonstrating that the vehicle did not have any impact on myelin processes in cuprizone-fed animals
Summary
Remyelination of lesions in the central nervous system contributes to neural repair following clinical relapses in multiple sclerosis. Simvastatin, a blood-brain barrierpermeable statin in multiple sclerosis clinical trials, has been shown to impact the in vitro processes that have been implicated in remyelination. Multiple sclerosis (MS) is characterized by inflammatory demyelinating lesions in the central nervous system (CNS) Remyelination of such lesions, recognized by histopathological and in vivo imaging techniques, is considered to contribute to neural repair following clinical relapses.. Experimental models of CNS demyelination indicate that remyelination is mediated by oligodendrocyte progenitor cells (OPCs), and requires their migration into the lesion and differentiation into mature myelinating phenotypes.. We have previously reported that short-term statin treatment of human and rodent OPCs and mature oligodendrocytes (OLGs) in vitro induces process outgrowth and differentiation via isoprenoid depletion..
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