Simvastatin regulates oligodendroglial process dynamics and survival.
Simvastatin, a lipophilic statin that crosses the blood-brain barrier, is being evaluated as a potential therapy for multiple sclerosis (MS) due to its anti-inflammatory properties. We assessed the effects of simvastatin on cultures of rat newborn and human fetal oligodendrocyte progenitor cells (OPCs) and human adult mature oligodendrocytes (OLGs) with respect to cellular events pertaining to myelin maintenance and repair. Short-term simvastatin treatment of OPCs (1 day) induced robust process extension, enhanced differentiation to a mature phenotype, and decreased spontaneous migration. These effects were reversed by isoprenoid products and mimicked with an inhibitor of Rho kinase (ROCK), the downstream effector of the isoprenylated protein RhoA GTPase. Prolonged treatment (2 days) caused process retraction that was rescued by cholesterol, and increased cell death (4 days) partially rescued by either cholesterol or isoprenoid co-treatment. In comparison, simvastatin treatment of human mature OLGs required a longer initial time course (2 days) to induce significant process outgrowth, mimicked by inhibiting ROCK. Prolonged treatment of mature OLGs was associated with process retraction (6 days) and increased cell death (8 days). Human-derived OPCs and mature OLGs demonstrated an increased sensitivity to simvastatin relative to the rodent cells, responding to nanomolar versus micromolar concentrations. Our findings indicate the importance of considering the short- and long-term effects of systemic immunomodulatory therapies on neural cells affected by the MS disease process. (c) 2006 Wiley-Liss, Inc.
Miron
Veronique E
VE
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Rajasekharan
Sathyanath
S
Jarjour
Andrew A
AA
Zamvil
Scott S
SS
Kennedy
Timothy E
TE
Antel
Jack P
JP
D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D013045:Species Specificity; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D013729:Terpenes / Q000009:adverse effects; D054460:rho-Associated Kinases
D000893:Anti-Inflammatory Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007155:Immunologic Factors; D047908:Intracellular Signaling Peptides and Proteins; D013729:Terpenes; D002784:Cholesterol; D019821:Simvastatin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases