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Simvastatin regulates oligodendroglial process dynamics and survival
Author(s) -
Miron Veronique E.,
Rajasekharan Sathyanath,
Jarjour Andrew A.,
Zamvil Scott S.,
Kennedy Timothy E.,
Antel Jack P.
Publication year - 2006
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20441
Subject(s) - simvastatin , biology , progenitor cell , rhoa , oligodendrocyte , myelin , microbiology and biotechnology , statin , pharmacology , stem cell , neuroscience , central nervous system , signal transduction , biochemistry
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. © 2006 Wiley‐Liss, Inc.