Simvastatin regulates oligodendroglial process dynamics and survival

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.

Netrin 1 and Dcc regulate oligodendrocyte process branching and membrane extension via Fyn and RhoA

“…9D), which is consistent with netrin 1 not increasing the activation of Cdc42 in oligodendrocytes. Inhibiting RhoA, or its downstream effector Rho kinase (Rock1/2), in oligodendrocytes increases process extension (Liang et al, 2004;Miron et al, 2007;Wolf et al, 2001). Interestingly, activation of Fyn in oligodendrocytes leads to inactivation of RhoA (Wolf et al, 2001), and we therefore investigated the possibility that netrin 1 might regulate RhoA activity in oligodendrocytes.…”

Cell Therapy for Multiple Sclerosis

“…More recently, pharmacologic induction of OPC differentiation by inhibition of RhoA-Rho-kinase II (ROCK-II), and/or protein kinase C signaling [108], or by anti-Leucine-rich repeats and Ig domain-containing, neurite outgrowth inhibitor (Nogo) receptor-interacting protein-1 (LINGO1) antibodies [109,110] accelerated remyelination. Statins and inhibitors of receptor tyrosine phosphatases are other pharmacologic agents that induce rodent [111] and human [112] oligodendrocyte differentiation. However, when tested in the cuprizone model of demyelination in vivo, statin therapy inhibited remyelination [113].…”

Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair

“…Subsequent studies with purified oligodendrocytes also reported that short-term treatment with simvastatin also induced differentiation to the mature phenotype via inactivation of RhoA. However, longer term treatment was associated with process retraction and cell death [69]. The observed increase in oligodendrocyte precursors, their differentiation and expression of myelin-related genes in mixed glial cultures and in EAE [10], as compared with the effects observed with purified oligodendrocytes [69], all indicate that trophic molecules secreted by astrocytes and microglia may potentiate the effects of statins.…”

“…However, longer term treatment was associated with process retraction and cell death [69]. The observed increase in oligodendrocyte precursors, their differentiation and expression of myelin-related genes in mixed glial cultures and in EAE [10], as compared with the effects observed with purified oligodendrocytes [69], all indicate that trophic molecules secreted by astrocytes and microglia may potentiate the effects of statins. The observed increased expression of transcription factors and trophic factors responsible for proliferation of oligodendrocyte progenitors, and transcription factors for their differentiation into myelin producing oligodendrocytes in lovastatin-treated animals during disease remission, may contribute to the observed remyelination in animals with EAE treated with lovastatin [10].…”

“…The expression of antibodies against oligodendrocytes and their progenitors [64,65], and activation of AMPA/kainite receptors by increased amounts of glutamate [66], are some of the factors that are reported to account for the observed demyelination in inflammatory areas in MS plaques. Reparative therapies with a potential to enhance remyelination, such as statins, provide a promising approach for myelin repair [10,68,69]. Higher numbers of oligodendrocyte progenitors in the spinal cords of animals with EAE treated with lovastatin and their observed proliferation and differentiation into myelin-producing cells document the potential of statins to repair demyelinated lesions [10].…”