Statins—Treatment Option for Central Nervous System Autoimmune Disease?

Weber, Martin; Steinman, Lawrence; Zamvil, Scott S.

doi:10.1016/j.nurt.2007.08.004

Cited by 21 publications

(18 citation statements)

References 77 publications

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“…The categories protein amino acid prenylation, protein prenylation and protein farnesylation are also linked to cholesterol biosynthesis. The genes with the highest importance scores in this group were farnesyltransferase‐α and the expressed sequence AA409500 related to farnesyltransferase‐β, which are involved in the post‐translational prenylation and farnesylation of several proteins, including the small GTP‐binding proteins RAB and RAS [43]. Both showed a mild decreasing expression pattern, reaching a –1.16 and –1.40‐fold down‐regulation at 196 dpi, respectively (EDGE, q < 0.001, and q = 0.002).…”

Section: Resultsmentioning

confidence: 99%

Machine learning approach identifies new pathways associated with demyelination in a viral model of multiple sclerosis

Ulrich

Kalkuhl

Deschl

et al. 2010

J Cellular Molecular Medi

106

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Theiler’s murine encephalomyelitis is an experimentally virus-induced inflammatory demyelinating disease of the spinal cord, displaying clinical and pathological similarities to chronic progressive multiple sclerosis. The aim of this study was to identify pathways associated with chronic demyelination using an assumption-free combined microarray and immunohistology approach. Movement control as determined by rotarod assay significantly worsened in Theiler’s murine encephalomyelitis -virus-infected SJL/J mice from 42 to 196 days after infection (dpi). In the spinal cords, inflammatory changes were detected 14 to 196 dpi, and demyelination progressively increased from 42 to 196 dpi. Microarray analysis revealed 1001 differentially expressed genes over the study period. The dominating changes as revealed by k-means and functional annotation clustering included up-regulations related to intrathecal antibody production and antigen processing and presentation via major histocompatibility class II molecules. A random forest machine learning algorithm revealed that down-regulated lipid and cholesterol biosynthesis, differentially expressed neurite morphogenesis and up-regulated toll-like receptor-4-induced pathways were intimately associated with demyelination as measured by immunohistology. Conclusively, although transcriptional changes were dominated by the adaptive immune response, the main pathways associated with demyelination included up-regulation of toll-like receptor 4 and down-regulation of cholesterol biosynthesis. Cholesterol biosynthesis is a rate limiting step of myelination and its down-regulation is suggested to be involved in chronic demyelination by an inhibition of remyelination.

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Section: Resultsmentioning

confidence: 99%

Machine learning approach identifies new pathways associated with demyelination in a viral model of multiple sclerosis

Ulrich

Kalkuhl

Deschl

et al. 2010

J Cellular Molecular Medi

106

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“…Nonetheless, important aspects of the etiopathogenesis of MS, including susceptibility genes, mechanisms of immune cell activation, immunoregulatory circuits, and mechanisms of axonal damage and repair have been elucidated by studying animal models. Moreover, several emerging MS therapies are currently in the preclinical testing phase in EAE or TMEV-IDD models (Weber et al, 2007). However, further improvements in the animal models used to study MS are required so that they may better reflect the pathogenesis and heterogeneity of this disease (Baker and Amor, 2011;Moreno et al, 2012).…”

Section: Unsuccessful Ms Therapiesmentioning

confidence: 99%

Viral models of multiple sclerosis: Neurodegeneration and demyelination in mice infected with Theiler's virus

Mecha

Carrillo‐Salinas

Mestre

et al. 2013

Progress in Neurobiology

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“…Because of the controversial discussion about the efficacy of statins, 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMG-CoA-reductase) inhibitors (93), as possible treatment of MS, further studies investigating the interaction between demyelinating diseases and cholesterol biosynthesis are required. In particular, studies that address the role of cholesterol biosynthesis on disease progression of MS, with particular emphasis on its potential beneficial effect on remyelination, are required.…”

Section: Introductionmentioning

confidence: 99%

Central Nervous System Demyelination and Remyelination is Independent from Systemic Cholesterol Level in Theiler's Murine Encephalomyelitis

Raddatz¹,

Sun²,

Brogden³

et al. 2015

Brain Pathology

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High dietary fat and/or cholesterol intake is a risk factor for multiple diseases and has been debated for multiple sclerosis. However, cholesterol biosynthesis is a key pathway during myelination and disturbances are described in demyelinating diseases. To address the possible interaction of dyslipidemia and demyelination, cholesterol biosynthesis gene expression, composition of the body's major lipid repositories and Paigen diet-induced, systemic hypercholesterolemia were examined in Theiler's murine encephalomyelitis (TME) using histology, immunohistochemistry, serum clinical chemistry, microarrays and high-performance thin layer chromatography. TME-virus (TMEV)-infected mice showed progressive loss of motor performance and demyelinating leukomyelitis. Gene expression associated with cholesterol biosynthesis was overall down-regulated in the spinal cord of TMEV-infected animals. Spinal cord levels of galactocerebroside and sphingomyelin were reduced on day 196 post TMEV infection. Paigen diet induced serum hypercholesterolemia and hepatic lipidosis. However, high dietary fat and cholesterol intake led to no significant differences in clinical course, inflammatory response, astrocytosis, and the amount of demyelination and remyelination in the spinal cord of TMEV-infected animals. The results suggest that down-regulation of cholesterol biosynthesis is a transcriptional marker for demyelination, quantitative loss of myelin-specific lipids, but not cholesterol occurs late in chronic demyelination, and serum hypercholesterolemia exhibited no significant effect on TMEV infection.

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Statins—Treatment Option for Central Nervous System Autoimmune Disease?

Cited by 21 publications

References 77 publications

Machine learning approach identifies new pathways associated with demyelination in a viral model of multiple sclerosis

Machine learning approach identifies new pathways associated with demyelination in a viral model of multiple sclerosis

Viral models of multiple sclerosis: Neurodegeneration and demyelination in mice infected with Theiler's virus

Central Nervous System Demyelination and Remyelination is Independent from Systemic Cholesterol Level in Theiler's Murine Encephalomyelitis

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