title: The red wine polyphenol resveratrol shows promising potential for the treatment of nucleus pulposus-mediated pain in vitro and in vivo.
abstract: METHODS
  Descriptive and mechanistic investigation of the anti-inflammatory and anticatabolic effect of resveratrol in intervertebral discs (IVDs) in vitro and of the analgetic effect in vivo.
  
  
  OBJECTIVE
  To determine whether resveratrol may be useful in treating nucleus pulposus (NP)-mediated pain.
  
  
  BACKGROUND
  Proinflammatory cytokines seem to be key mediators in the development of NP-mediated pain. Patients with discogenic or radiculopathic pain may substantially benefit from anti-inflammatory substances that could be used in a minimal-invasive treatment approach. Resveratrol, a polyphenolic phytoalexin found in red wine exhibits anti-inflammatory effects in various cell types and tissues, but no data exists so far with regards to the IVD in the context of low back and leg pain.
  
  
  METHODS
  In part 1, the anti-inflammatory and anticatabolic effect of resveratrol was investigated in a cell culture model on interleukin 1β (IL-1β) prestimulated human IVD cells on the gene and protein expression level. In part 2, the molecular mechanisms underlying the effects observed upon resveratrol treatment were investigated (toll-like receptors, nuclear factor κB, sirtuin 1 (SIRT1), mitogen-activated protein (MAP) kinases p38/ERK/JNK). In part 3, the analgetic effects of resveratrol were investigated in vivo using a rodent model of radiculopathy and von Frey filament testing. All quantitative data were statistically evaluated either by Mann-Whitney U test or by one-way analysis of variance and Bonferroni post hoc testing (P < 0.05).
  
  
  RESULTS
  In vitro, resveratrol exhibited an anti-inflammatory and anticatabolic effect on the messenger RNA and protein level for IL-6, IL-8, MMP1, MMP3 and MMP13. This effect does not seem to be mediated via the MAP kinase pathways (p38, ERK, JNK) or via the NF-κB/SIRT1 pathway, although toll-like receptor 2 was regulated to a minor extent. In vivo, resveratrol significantly reduced pain behavior triggered by application of NP tissue on the dorsal root ganglion for up to 14 days.
  
  
  CONCLUSIONS
  Resveratrol was able to reduce levels of proinflammatory cytokines in vitro and showed analgetic potential in vivo. A decrease in proinflammatory cytokines may possibly be the underlying mechanism of pain reduction observed in vivo. Resveratrol seems to have considerable potential for the treatment of NP-mediated pain and may thus be an alternative to other currently discussed (biological) treatment options.
authors.affiliation: Spine Research Group, Competence Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Zurich, Switzerland. karin.wuertz@cabmm.uzh.ch
authors.forename: Karin
authors.initials: K
authors.lastname: Wuertz
authors.forename: Lilian
authors.initials: L
authors.lastname: Quero
authors.forename: Miho
authors.initials: M
authors.lastname: Sekiguchi
authors.forename: Marina
authors.initials: M
authors.lastname: Klawitter
authors.forename: Andreas
authors.initials: A
authors.lastname: Nerlich
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Konno
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Norbert
authors.initials: N
authors.lastname: Boos
mesh_terms: D000328:Adult; D000368:Aged; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007403:Intervertebral Disc / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010147:Pain Measurement; D012333:RNA, Messenger / Q000378:metabolism; D011843:Radiculopathy / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014920:Wine; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; C508606:CXCL8 protein, human; C508600:IL6 protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D013267:Stilbenes; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol