Journal of Neuroimmune Pharmacology

, Volume 7, Issue 4, pp 1002–1016 | Cite as

A Cannabigerol Quinone Alleviates Neuroinflammation in a Chronic Model of Multiple Sclerosis

  • Aitor G. Granja
  • Francisco Carrillo-Salinas
  • Alberto Pagani
  • María Gómez-Cañas
  • Roberto Negri
  • Carmen Navarrete
  • Miriam Mecha
  • Leyre Mestre
  • Bend L. Fiebich
  • Irene Cantarero
  • Marco A. Calzado
  • Maria L. Bellido
  • Javier Fernandez-Ruiz
  • Giovanni Appendino
  • Carmen Guaza
  • Eduardo Muñoz
ORIGINAL ARTICLE

Abstract

Phytocannabinoids like ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD) show a beneficial effect on neuroinflammatory and neurodegenerative processes through cell membrane cannabinoid receptor (CBr)-dependent and -independent mechanisms. Natural and synthetic cannabinoids also target the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ), an attractive molecular target for the treatment of neuroinflammation. As part of a study on the SAR of phytocannabinoids, we have investigated the effect of the oxidation modification in the resorcinol moiety of cannabigerol (CBG) on CB1, CB2 and PPARγ binding affinities, identifying cannabigerol quinone (VCE-003) as a potent anti-inflammatory agent. VCE-003 protected neuronal cells from excitotoxicity, activated PPARγ transcriptional activity and inhibited the release of pro-inflammatory mediators in LPS-stimulated microglial cells. Theiler’s murine encephalomyelitis virus (TMEV) model of multiple sclerosis (MS) was used to investigate the anti-inflammatory activity of this compound in vivo. Motor function performance was evaluated and the neuroinflammatory response and gene expression pattern in brain and spinal cord were studied by immunostaining and qRT-PCR. We found that VCE-003 ameliorated the symptoms associated to TMEV infection, decreased microglia reactivity and modulated the expression of genes involved in MS pathophysiology. These data lead us to consider VCE-003 to have high potential for drug development against MS and perhaps other neuroinflammatory diseases.

Keywords

Cannabinoids Cannabigerol PPARγ Neuroinflammation Multiple sclerosis 

Abbreviations

CBD

Cannabidiol

CBG

Cannabigerol

EAE

Experimental autoimmune encephalomyelitis

Foxp3

Forkhead box P3

Icam-1

Intercellular adhesion molecule 1

IDD

Induced Demyelinating Disease

PGE2

Prostaglandin E2

PPAR

Peroxisome proliferator-activated receptor

RSZ

Rosiglitazone

THC

Δ9-tetrahydrocannabinol

TMEV

Theiler’s Murine Encephalomyelitis Virus

VLA-4

Very late antigen 4

Supplementary material

11481_2012_9399_MOESM1_ESM.doc (36 kb)
ESM 1(DOC 36 kb)
11481_2012_9399_MOESM2_ESM.pptx (1.4 mb)
ESM 2(PPTX 1409 kb)

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Aitor G. Granja
    • 1
  • Francisco Carrillo-Salinas
    • 2
  • Alberto Pagani
    • 3
  • María Gómez-Cañas
    • 4
  • Roberto Negri
    • 3
  • Carmen Navarrete
    • 1
  • Miriam Mecha
    • 2
  • Leyre Mestre
    • 2
  • Bend L. Fiebich
    • 5
    • 6
  • Irene Cantarero
    • 7
  • Marco A. Calzado
    • 7
  • Maria L. Bellido
    • 1
  • Javier Fernandez-Ruiz
    • 4
  • Giovanni Appendino
    • 3
  • Carmen Guaza
    • 2
  • Eduardo Muñoz
    • 7
  1. 1.Vivacell Biotechnology España S.L. Parque Científico Tecnológico Rabanales 21CórdobaSpain
  2. 2.Instituto CajalCSICMadridSpain
  3. 3.Dipartimento di Scienze FarmaceuticheUniversità del Piemonte OrientaleNovaraItaly
  4. 4.Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Facultad de MedicinaUniversidad ComplutenseMadridSpain
  5. 5.Neurochemistry Research Group, Department of PsychiatryUniversity of Freiburg Medical SchoolFreiburgGermany
  6. 6.VivaCell Biotechnology GmbHDenzlingenGermany
  7. 7.Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Departamento de Biología Celular, Fisiología e InmunologíaUniversidad de CórdobaCórdobaSpain

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