Simvastatin regulates oligodendroglial process dynamics and survival

Veronique E Miron, Sathyanath Rajasekharan, Andrew A Jarjour, Scott S Zamvil, Timothy E Kennedy, Jack P Antel

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)130-43
Number of pages14
JournalGlia
Volume55
Issue number2
DOIs
Publication statusPublished - 15 Jan 2007

Keywords

  • Terpenes
  • Anti-Inflammatory Agents
  • Nerve Fibers, Myelinated
  • rho-Associated Kinases
  • Animals
  • Immunologic Factors
  • Intracellular Signaling Peptides and Proteins
  • Oligodendroglia
  • Humans
  • Cell Survival
  • Rats
  • Multiple Sclerosis
  • Nerve Regeneration
  • Stem Cells
  • Cell Movement
  • Dose-Response Relationship, Drug
  • Simvastatin
  • Cell Differentiation
  • Cholesterol
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Central Nervous System
  • Protein-Serine-Threonine Kinases
  • Animals, Newborn
  • Rats, Sprague-Dawley
  • Cells, Cultured
  • Cell Death
  • Species Specificity

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