Statins as potential therapeutic agents in multiple sclerosis

Stüve, Olaf; Prod’homme, Thomas; Youssef, Sawsan; Dunn, Shannon; Neuhaus, Oliver; Weber, Martin; Hartung, Hans Peter; Steinman, Lawrence; Zamvil, Scott S.

doi:10.1007/s11910-004-0044-2

Cited by 11 publications

(5 citation statements)

References 90 publications

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“…Another transcript with elevated expression was Cd36, a multiligand scavenger receptor expressed by the cell of the monocyte/ macrophage lineage (including microglia) that plays important roles in cell attachment, motility, and proliferation as well as atherosclerosis, inflammation, thrombosis, TGF-␤ activation, neurite outgrowth, and angiogenesis (29). Statins, an effective cholesterollowering family of drugs, are highly effective in treating EAE, and clinical trials in MS patients are currently under way (30,31). Surprisingly, it has been recently shown that statins are potent activators of Cd36 transcription and translation in human monocytes (32).…”

Section: Discussionmentioning

confidence: 99%

Modular Transcriptional Activity Characterizes the Initiation and Progression of Autoimmune Encephalomyelitis

Baranzini

Bernard

Oksenberg

2005

The Journal of Immunology

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Murine experimental autoimmune encephalomyelitis is a well-established model that recapitulates many clinical and physiopathological aspects of multiple sclerosis (MS). An important conceptual development in the understanding of both experimental autoimmune encephalomyelitis and MS pathogenesis has been the compartmentalization of the mechanistic process into two distinct but overlapping and connected phases, inflammatory and neurodegenerative. However, the dynamics of CNS transcriptional changes that underlie the development and regression of the phenotype are not well understood. Our report presents the first high frequency longitudinal study looking at the earliest transcriptional changes in the CNS of NOD mice immunized with myelin oligodendrocyte glycoprotein 35-55 in CFA. Microarray-based gene expression profiling and histopathological analysis were performed from spinal cord samples obtained at 13 time points around the first clinical symptom (every other day until day 11 and every day onward until day 19 postimmunization). Advanced statistics and data-mining algorithms were used to identify expression signatures that correlated with disease stage and histological profiles. Discrete phases of neuroinflammation were accompanied by distinctive expression signatures, in which altered immune to neural gene expression ratios were observed. By using high frequency gene expression analysis we captured expression profiles that were characteristic of the transition from innate to adaptive immune response in this experimental paradigm between days 11 and 12 postimmunization. Our study demonstrates the utility of large-scale transcriptional studies and advanced data mining to decipher complex biological processes such as those involved in MS and other neurodegenerative disoders. The Journal of Immunology, 2005, 174: 7412-7422.C hronic autoimmune diseases like multiple sclerosis (MS) 3 develop over the course of months or years without exhibiting any observable phenotype. By following patterns of gene expression over time in suitable and well-controlled experimental models, it should be possible to identify early pathogenic mechanisms that precede symptoms and to unravel regulatory events undetectable at the clinical or pathological level. Experimental autoimmune encephalomyelitis (EAE) can be induced in a variety of animal species, including nonhuman primates, by active immunization with myelin proteins or their peptide derivatives, as well as by adoptive transfer of activated CD4 ϩ T cells specific for myelin components (1-6). The encephalitogenic challenge compromises blood-brain barrier (BBB) integrity and produces CNS inflammation and neurodegeneration leading to neurologic disease. Ataxia and paralysis occurs first in the tail and hind limbs, and progressive deterioration later affects the forelimbs, eventually causing death. From all available EAE murine models, the one induced by myelin oligodendrocyte glycoprotein (MOG) in the NOD background is perhaps the most adequate for a time-controlled experiment, in ...

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Section: Discussionmentioning

confidence: 99%

Modular Transcriptional Activity Characterizes the Initiation and Progression of Autoimmune Encephalomyelitis

Baranzini

Bernard

Oksenberg

2005

The Journal of Immunology

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“…Statins downregulate transporter 1, which may affect the so-called reverse cholesterol transport system [61], but could also alter peptide presentation by APCs. It is possible that some of the effects of statins in EAE and potentially in MS could be due to this activity [62,63].…”

Section: Major Histocompatibility Complex (Mhc)mentioning

confidence: 99%

Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for immune-related molecules by central nervous system mixed glial cell cultures

et al. 2006

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Cytokines secreted within the central nervous system (CNS) are important in the development of multiple sclerosis (MS) lesions. The balance between Th1, monocyte/macrophage (M/M) and Th2 cytokines in the CNS may be pivotal in determining the outcome of lesion development. We examined the effects of mixtures of cytokines on gene expression by CNS glial cells, as mixtures of cytokines are present in MS lesions, which in turn contain mixtures of glial cells. In this initial analysis by gene array, we examined changes at 6 hours to identify early changes in gene expression that represent primary responses to the cytokines. Rat glial cells were incubated with mixtures of Th1, M/M and Th2 cytokines for 6 hours and examined for changes in early gene expression employing microarray gene chip technology. A minimum of 814 genes were differentially regulated by one or more of the cytokine mixtures in comparison to controls, including changes in expression in a large number of genes for immune system-related proteins. Expression of the proteins for these genes likely influences development and inhibition of MS lesions as well as protective and regenerative processes. Analysing gene expression for the effects of various combinations of exogenous cytokines on glial cells in the absence of the confounding effects of inflammatory cells themselves should increase our understanding of cytokine-induced pathways in the CNS.

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“…Much of the current understanding of the treatment comes from the Optic Neuritis Treatment Trial (ONTT). 4 In recent years, small-scale clinical trials have indicated that statins or 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors exert pleiotropic immunomodulatory effects, with potential therapeutic implications in MS. [5][6][7][8][9][10] The mechanism by which statins may play a role in autoimmunity involves the inhibition of HMGCoA reductase. Besides the biosynthesis of cholesterol, this enzyme regulates the biosynthesis of isoprenoids, which results in a decrease of autoimmune responses.…”

Section: Introductionmentioning

confidence: 99%

Simvastatin improves final visual outcome in acute optic neuritis: a randomized study

et al. 2011

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Statins as potential therapeutic agents in multiple sclerosis

Cited by 11 publications

References 90 publications

Modular Transcriptional Activity Characterizes the Initiation and Progression of Autoimmune Encephalomyelitis

Modular Transcriptional Activity Characterizes the Initiation and Progression of Autoimmune Encephalomyelitis

Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for immune-related molecules by central nervous system mixed glial cell cultures

Simvastatin improves final visual outcome in acute optic neuritis: a randomized study

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