What has Chilean red wine and B cells have in common?

Could resveratrol be a treatment for MS? #MSBlog #MSResearch

"Just got back from a neurology meeting in Santiago, Chile. I wonderful country with wonderful guests and very hospitable hosts. After reading the article below two things about my short stay in Chile stood out; (1) a dinner discussion, or debate, on the pathogenesis (abnormal biological mechanisms that underlie a disease) of MS and (2) the remarkable red wine that is produced in Chile (I brought 3 bottles back with me).  You may rightly ask what has red wine go to do with the pathogenesis of MS? Read on!"

"When you list the cellular targets of all the highly effective disease-modifying therapies in MS the only cell common to them all is the B-cell. This is one of the reasons why I think the B-cell, and I have done so for sometime, is the culprit in MS. The group below have found that a specific micro-RNA, a member of a relatively newly discovered family of intra-cellular regulatory molecules, is abnormally regulated in B cells in MSers compared to healthy controls. They show that this mircro-RNA works via a pathway that controls the production of potent pro-inflammatory cytokines (molecules that cells produce as part of inflammation). What is fascinating is that resveratrol, a metabolite of plants, normalised this abnormal cytokine production in B cells. Could resveratrol be used to treat MS?"

"Resveratrol is found in plants and is concentrated in red wine; white wine has much less resveratrol because red wine is fermented with the skins, allowing the wine to extract the resveratrol, whereas white wine is generally fermented after the skins have been removed. Resveratrol is one of those food supplements that has recently been oversold as being the panacea for everything including an anti-ageing compound. The wine industry, in particular French winemakers, have been guilty of using the resveratrol story to promote red wine consumption. Whether or not you can get sufficiently high levels of resveratrol in your blood from drinking red wine, or taking supplements, to down-regulate aberrant B-cell function in MSers needs further study. In other words resveratrol needs to be tested like any other drug to see if it has disease-modifying effects in MS. The concept of using resveratol to treat MS and other neuro-degenerative diseases is not new, in fact there is a large literature on this already. I have appended an abstract showing it has neuroprotective effects in EAE."

Miyazaki et al. A Novel MicroRNA-132-Surtuin-1 Axis Underlies Aberrant B-cell Cytokine Regulation in Patients with Relapsing-Remitting Multiple Sclerosis. PLoS One. 2014 Aug 19;9(8):e105421. doi: 10.1371/journal.pone.0105421. eCollection 2014.

Background: Clinical trial results demonstrating that B-cell depletion substantially reduces new relapses in MSers have established that B cells play a role in the pathophysiology of MS relapses. The same treatment appears not to impact antibodies directed against the central nervous system, which underscores the contribution of antibody-independent functions of B cells to disease activity. One mechanism by which B cells are now thought to contribute to MS activity is by over-activating T cells, including through aberrant expression of B cell pro-inflammatory cytokines. However, the mechanisms underlying the observed B cell cytokine dysregulation in MS remain unknown. 

Hypothesis: We hypothesized that aberrant expression of particular microRNAs might be involved in the dysregulated pro-inflammatory cytokine responses of B cells of MSers. 

Methods & Results: Through screening candidate microRNAs in activated B cells of MSers and matched healthy subjects, we discovered that abnormally increased secretion of lymphotoxin and tumor necrosis factor α by MS B cells is associated with abnormally increased expression of miR-132. Over-expression of miR-132 in normal B cells significantly enhanced their production of lymphotoxin and tumor necrosis factor α. The over-expression of miR-132 also suppressed the miR-132 target, sirtuin-1. We confirmed that pharmacological inhibition of sirtuin-1 in normal B cells induces exaggerated lymphotoxin and tumor necrosis factor α production, while the abnormal production of these cytokines by MS B cells can be normalized by resveratrol, a sirtuin-1 activator. 

Conclusion: These results define a novel miR-132-sirtuin-1 axis that controls pro-inflammatory cytokine secretion by human B cells, and demonstrate that a dysregulation of this axis underlies abnormal pro-inflammatory B cell cytokine responses in patients with MS.

"What's a micro-RNA? There are loads of posts on the blog but in brief it is small RNA molecule that controls the production of other proteins from within a cell. In other words it is an intracellular regulator."

  1. Multiple Sclerosis Research: Research MicroRNA 15 Jan 2012
  2. Multiple Sclerosis Research: Research: MicroRNA in ... 27 Jan 2012
  3. Multiple Sclerosis Research: MicroRNA could affect the ...18 Mar 2014
  4. Multiple Sclerosis Research: MicroRNA affect Progressive MS 19 Dec 2013
  5. Research MicroRNA as new targets for treatment in MS 22 Apr 2013
  6. Multiple Sclerosis Research: Research: MicroRNA in the ...17 Mar 2013
Fonseca-Kelly et al. Resveratrol neuroprotection in a chronic mouse model of multiple sclerosis. Front Neurol. 2012 May 24;3:84. doi: 10.3389/fneur.2012.00084. eCollection 2012.

Background: Resveratrol is a naturally occurring polyphenol that activates SIRT1, an NAD-dependent deacetylase. SRT501, a pharmaceutical formulation of resveratrol with enhanced systemic absorption, prevents neuronal loss without suppressing inflammation in mice with relapsing experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). In contrast, resveratrol has been reported to suppress inflammation in chronic EAE, although neuroprotective effects were not evaluated. 

Objective: The current studies examine potential neuroprotective and immunomodulatory effects of resveratrol in chronic EAE induced by immunization with myelin oligodendroglial glycoprotein peptide in C57/Bl6 mice. 

Methods & Results: Effects of two distinct formulations of resveratrol administered daily orally were compared.Resveratrol delayed the onset of EAE compared to vehicle-treated EAE mice, but did not prevent or alter the phenotype of inflammation in spinal cords or optic nerves. Significant neuroprotective effects were observed, with higher numbers of retinal ganglion cells found in eyes of resveratrol-treated EAE mice with optic nerve inflammation. Results demonstrate that resveratrol prevents neuronal loss in this chronic demyelinating disease model, similar to its effects in relapsing EAE. Differences in immunosuppression compared with prior studies suggest that immunomodulatory effects may be limited and may depend on specific immunization parameters or timing of treatment. 

Conclusion: Importantly, neuroprotective effects can occur without immunosuppression, suggesting a potential additive benefit of resveratrol in combination with anti-inflammatory therapies for MS.

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