Belén Palomares1,2,3, Martín Garrido-Rodriguez1,2,3, Claudia Gonzalo-Consuegra4,5,6, María Gómez-Cañas4,5,6, Suwipa Saen-Oon7, Robert Soliva7, Juan A Collado8, Javier Fernández-Ruiz4,5,6, Gaetano Morello9, Marco A Calzado1,2,3, Giovanni Appendino10, Eduardo Muñoz1,2,3. 1. Maimonides Biomedical Research Institute of Córdoba, University of Córdoba, Córdoba, Spain. 2. Department of Cellular Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain. 3. Reina Sofía University Hospital, Córdoba, Spain. 4. Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain. 5. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. 6. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. 7. Nostrum Biodiscovery, Barcelona, Spain. 8. Emerald Health Biotechnology, Córdoba, Spain. 9. Emerald Health Natural, Vancouver, British Columbia, Canada. 10. Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Novara, Italy.
Abstract
BACKGROUND AND PURPOSE: Δ9 -Tetrahydrocannabinolic acid (Δ9 -THCA-A), the precursor of Δ9 -THC, is a non-psychotropic phytocannabinoid that shows PPARγ agonist activity. Here, we investigated the ability of Δ9 -THCA-A to modulate the classic cannabinoid CB1 and CB2 receptors and evaluated its anti-arthritis activity in vitro and in vivo. EXPERIMENTAL APPROACH: Cannabinoid receptors binding and intrinsic activity, as well as their downstream signalling, were analysed in vitro and in silico. The anti-arthritis properties of Δ9 -THCA-A were studied in human chondrocytes and in the murine model of collagen-induced arthritis (CIA). Plasma disease biomarkers were identified by LC-MS/MS based on proteomic and elisa assays. KEY RESULTS: Functional and docking analyses showed that Δ9 -THCA-A can act as an orthosteric CB1 receptor agonist and also as a positive allosteric modulator in the presence of CP-55,940. Also, Δ9 -THCA-A seemed to be an inverse agonist for CB2 receptors. In vivo, Δ9 -THCA-A reduced arthritis in CIA mice, preventing the infiltration of inflammatory cells, synovium hyperplasia, and cartilage damage. Furthermore, Δ9 -THCA-A inhibited expression of inflammatory and catabolic genes on knee joints. The anti-arthritic effect of Δ9 -THCA-A was blocked by either SR141716 or T0070907. Analysis of plasma biomarkers, and determination of cytokines and anti-collagen antibodies confirmed that Δ9 -THCA-A mediated its activity mainly through PPARγ and CB1 receptor pathways. CONCLUSION AND IMPLICATIONS: Δ9 -THCA-A modulates CB1 receptors through the orthosteric and allosteric binding sites. In addition, Δ9 -THCA-A exerts anti-arthritis activity through CB1 receptors and PPARγ pathways, highlighting its potential for the treatment of chronic inflammatory diseases such as rheumatoid arthritis.
BACKGROUND AND PURPOSE: Δ9 -Tetrahydrocannabinolic acid (Δ9 -THCA-A), the precursor of Δ9 -THC, is a non-psychotropic phytocannabinoid that shows PPARγ agonist activity. Here, we investigated the ability of Δ9 -THCA-A to modulate the classic cannabinoid CB1 and CB2 receptors and evaluated its anti-arthritis activity in vitro and in vivo. EXPERIMENTAL APPROACH: Cannabinoid receptors binding and intrinsic activity, as well as their downstream signalling, were analysed in vitro and in silico. The anti-arthritis properties of Δ9 -THCA-A were studied in human chondrocytes and in the murine model of collagen-induced arthritis (CIA). Plasma disease biomarkers were identified by LC-MS/MS based on proteomic and elisa assays. KEY RESULTS: Functional and docking analyses showed that Δ9 -THCA-A can act as an orthosteric CB1 receptor agonist and also as a positive allosteric modulator in the presence of CP-55,940. Also, Δ9 -THCA-A seemed to be an inverse agonist for CB2 receptors. In vivo, Δ9 -THCA-A reduced arthritis in CIA mice, preventing the infiltration of inflammatory cells, synovium hyperplasia, and cartilage damage. Furthermore, Δ9 -THCA-A inhibited expression of inflammatory and catabolic genes on knee joints. The anti-arthritic effect of Δ9 -THCA-A was blocked by either SR141716 or T0070907. Analysis of plasma biomarkers, and determination of cytokines and anti-collagen antibodies confirmed that Δ9 -THCA-A mediated its activity mainly through PPARγ and CB1 receptor pathways. CONCLUSION AND IMPLICATIONS: Δ9 -THCA-A modulates CB1 receptors through the orthosteric and allosteric binding sites. In addition, Δ9 -THCA-A exerts anti-arthritis activity through CB1 receptors and PPARγ pathways, highlighting its potential for the treatment of chronic inflammatory diseases such as rheumatoid arthritis.
Authors: Christoph Grebner; Daniel Lecina; Victor Gil; Johan Ulander; Pia Hansson; Anita Dellsen; Christian Tyrchan; Karl Edman; Anders Hogner; Victor Guallar Journal: Biophys J Date: 2017-03-28 Impact factor: 4.033
Authors: John M McPartland; Christa MacDonald; Michelle Young; Phillip S Grant; Daniel P Furkert; Michelle Glass Journal: Cannabis Cannabinoid Res Date: 2017-05-01
Authors: Belén Palomares; Martín Garrido-Rodriguez; Claudia Gonzalo-Consuegra; María Gómez-Cañas; Suwipa Saen-Oon; Robert Soliva; Juan A Collado; Javier Fernández-Ruiz; Gaetano Morello; Marco A Calzado; Giovanni Appendino; Eduardo Muñoz Journal: Br J Pharmacol Date: 2020-07-08 Impact factor: 8.739
Authors: Melissa J Benson; Lyndsey L Anderson; Ivan K Low; Jia Lin Luo; Richard C Kevin; Cilla Zhou; Iain S McGregor; Jonathon C Arnold Journal: Cannabis Cannabinoid Res Date: 2020-09-09