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

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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.

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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

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Acknowledgments

This work was supported supported by the MINECO grants IPT-2011-0861-900000 (EM and CG), SAF2010-19292 (EM), SAF2010-17501 (CG), SAF2009-11847 (JFR), S2010/BMD-2308 (CG and JFR) and by RETICS RIS RD06/0006/0028 and REEM RD07/0060/0010. Finally, we thank Ms. Carmen Cabrero-Doncel for her assistance with the manuscript.

Conflict of interest

MLB, GA and EM have filed a PCT application “Cannabinoid quinone derivatives” (application number PCT-03494). All the other authors declare no conflict of interest.

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Authors and Affiliations

  1. Vivacell Biotechnology España S.L. Parque Científico Tecnológico Rabanales 21, c/Cecilia Payne, Parcela ID 8.1, 14014, Córdoba, Spain

    Aitor G. Granja, Carmen Navarrete & Maria L. Bellido

  2. Instituto Cajal, CSIC, Avda. Doctor Arce, 37, 28002, Madrid, Spain

    Francisco Carrillo-Salinas, Miriam Mecha, Leyre Mestre & Carmen Guaza

  3. Dipartimento di Scienze Farmaceutiche, Università del Piemonte Orientale, Via Bovio 6, 28100, Novara, Italy

    Alberto Pagani, Roberto Negri & Giovanni Appendino

  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 Medicina, Universidad Complutense, 28040, Madrid, Spain

    María Gómez-Cañas & Javier Fernandez-Ruiz

  5. Neurochemistry Research Group, Department of Psychiatry, University of Freiburg Medical School, Hauptstrasse 5, 79104, Freiburg, Germany

    Bend L. Fiebich

  6. VivaCell Biotechnology GmbH, Ferdinand-Porsche-Str. 5, 79211, Denzlingen, Germany

    Bend L. Fiebich

  7. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, c/María, Virgen y Madre s/n, 14004, Córdoba, Spain

    Irene Cantarero, Marco A. Calzado & Eduardo Muñoz

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  1. Aitor G. Granja
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Correspondence to Eduardo Muñoz.

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Granja, A.G., Carrillo-Salinas, F., Pagani, A. et al. A Cannabigerol Quinone Alleviates Neuroinflammation in a Chronic Model of Multiple Sclerosis. J Neuroimmune Pharmacol 7, 1002–1016 (2012). https://doi.org/10.1007/s11481-012-9399-3

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