Vitamin D and remyelination in multiple sclerosis

Matías‐Guiu, Jordi A.; Oreja‐Guevara, Celia; Gómez‐Pinedo, Ulises

doi:10.1016/j.nrleng.2016.05.010

Cited by 22 publications

(12 citation statements)

References 125 publications

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“…Based on the evidence that remyelination failure is more commonly associated with the impairment of the final stage of oligodendrocyte developmental program25, strategies to enhance remyelination are frequently designed to promote OPC differentiation into new myelinating oligodendrocytes31. However, several remyelinating molecules have been described to promote both proliferation and differentiation323334 or proliferation alone35. These two processes are not mutually exclusive for the progression of oligodendrocyte lineage; indeed cAMP response element-binding protein (CREB), implicated in controlling myelin gene expression and oligodendrocyte generation, participates in the regulation of both OPC proliferation36 and differentiation37.…”

Section: Discussionmentioning

confidence: 99%

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

Eleuteri

Olla

Veroni

et al. 2017

Sci Rep

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There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds’ activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

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Section: Discussionmentioning

confidence: 99%

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

Eleuteri

Olla

Veroni

et al. 2017

Sci Rep

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“…The contribution of immunopathogenesis as a determinant of MS is supported by large‐scale genetic studies showing linkages to multiple immune genes, especially to the major histocompatability complex (MHC) locus on chromosome 6 (Caillier et al, ; Mangalam, Rajagopalan, Taneja, & David, ). Several environmental risk factors implicated in MS include reduced sunlight exposure and vitamin D 3 serum levels as well as cigarette smoking and specific infections (Matias‐Guiu, Oreja‐Guevara, Matias‐Guiu, & Gomez‐Pinedo, ; Morandi, Tarlinton, & Gran, ; Watad et al, ). Both innate and adaptive immunity participate in the pathogenesis of MS and its established model, experimental autoimmune encephalomyelitis (EAE), as indicated by the presence of activated lymphocytes and increased cytokine and chemokine production by macrophages, microglia and astrocytes (Gomez Perdiguero, Schulz, & Geissmann, ; Grebing et al, ; Hendriks, Teunissen, de Vries, & Dijkstra, ; Mayo, Quintana, & Weiner, ).…”

Section: Introductionmentioning

confidence: 99%

Suppressed oligodendrocyte steroidogenesis in multiple sclerosis: Implications for regulation of neuroinflammation

Boghozian

McKenzie

Saito

et al. 2017

Glia

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Neurosteroids are reported to exert anti-inflammatory effects in several neurological disorders. We investigated the expression and actions of the neurosteroid, dehydroepiandrosterone (DHEA), and its more stable 3β-sulphated ester, DHEA-S, in MS and associated experimental models. CNS tissues from patients with MS and animals with experimental autoimmune encephalomyelitis (EAE) displayed reduced DHEA concentrations, accompanied by diminished expression of the DHEA-synthesizing enzyme CYP17A1 in oligodendrocytes (ODCs), in association with increased expression of inflammatory genes including interferon (IFN)-γ and interleukin (IL)-1β. CYP17A1 was expressed variably in different human neural cell types but IFN-γ exposure selectively reduced CYP17A1 detection in ODCs. DHEA-S treatment reduced IL-1β and -6 release from activated human myeloid cells with minimal effect on lymphocyte viability. Animals with EAE receiving DHEA-S treatment showed reduced Il1b and Ifng transcript levels in spinal cord compared to vehicle-treated animals with EAE. DHEA-S treatment also preserved myelin basic protein immunoreactivity and reduced axonal loss in animals with EAE, relative to vehicle-treated EAE animals. Neurobehavioral deficits were reduced in DHEA-S-treated EAE animals compared with vehicle-treated animals with EAE. Thus, CYP17A1 expression in ODCs and its product DHEA were downregulated in the CNS during inflammatory demyelination while DHEA-S provision suppressed neuroinflammation, demyelination, and axonal injury that was evident as improved neurobehavioral performance. These findings indicate that DHEA production is an immunoregulatory pathway within the CNS and its restoration represents a novel treatment approach for neuroinflammatory diseases.

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“…VD insufficiency is associated with the active phenotype of IBD. It has also been suggested that VD 4 supplementation may ameliorate several immune-related diseases including multiple sclerosis, experimental autoimmune encephalomyelitis and IBD [11][12][13]. Recently, the role of VD and VDR in most chronic diseases such as cardiovascular disease, diabetes, cancers, autoimmune diseases, and infectious diseases among others, has been the subject of much attention as well as its role in regulating gene transcription [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

VDR Pathway-Specific Dose-Related Effects of 1,25(OH)2D3 on Salmonella typhimurium-induced Mouse Colitis

Qiu¹,

Zhang²,

Li³

et al. 2020

Preprint

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Background: Whether and how 1,25(OH)2D3 supplementation influences VDRs in experimental mice with colitis remains to be seen. To explore the effect of 1,25(OH)2D3 on S. typhimurium colitis through the VDR pathway and to discover the role of VDR in its action. Methods: We established a mouse UC model induced by S. typhimurium. After streptococcal typhus infection, the mice were fasted for 12 hours. Blood was collected by the eyeball extraction method, and then sacrificed by cervical dislocation, specimens were collected for corresponding indicators. Results: Mice exposed to S. typhimurium infection developed signs of acute colitis. After HE staining were performed on the diseased colons from the mice. high dose VD supplementation, the pathological colonic damage did not improve in the mice, and there was no statistical difference between the groups with VD deficiency (P>0.05). VDR expression in the UC group treated with Salmonella was higher than that in the control group, a statistically significant difference (P<0.01). Compared with the VDD+UC group, VDR expression rose in both the LVDS+UC group and the HVDS+UC group, with VDR protein expression being highest after high dose VD supplementation (P<0.01). Compared with the control and the UC groups, the VDR mRNA expression level in the VDD+UC group was significantly higher, and the colon VDR mRNA expression level decreased after active VD supplementation (Fig.7C). Conclusions: Our data suggest the need for defining the accurate 1,25(OH)2D3 dose limits that induce an anti-inflammatory effect as current data indicate that higher doses would produce an inflammatory response.

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Vitamin D and remyelination in multiple sclerosis

Cited by 22 publications

References 125 publications

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

Suppressed oligodendrocyte steroidogenesis in multiple sclerosis: Implications for regulation of neuroinflammation

VDR Pathway-Specific Dose-Related Effects of 1,25(OH)2D3 on Salmonella typhimurium-induced Mouse Colitis

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