RT Journal Article
T1 Δ9‐Tetrahydrocannabinolic acid alleviates collagen‐induced arthritis: Role of PPARγ and CB1 receptors
A1 Palomares, Belén
A1 Gonzalo Consuegra, Claudia
A1 Gómez Cañas, María
A1 Fernández Ruiz, José Javier
A1 Muñoz, Eduardo
AB Background and Purpose: Δ9-Tetrahydrocannabinolic acid (Δ9-THCA-A), the precur sor of Δ9-THC, is a non-psychotropic phytocannabinoid that shows PPARγ agonistactivity. Here, we investigated the ability of Δ9-THCA-A to modulate the classic can nabinoid CB1 and CB2 receptors and evaluated its anti-arthritis activity in vitro andin vivo.Experimental Approach: Cannabinoid receptors binding and intrinsic activity, as wellas their downstream signalling, were analysed in vitro and in silico. The anti-arthritisproperties of Δ9-THCA-A were studied in human chondrocytes and in the murinemodel of collagen-induced arthritis (CIA). Plasma disease biomarkers were identifiedby LC-MS/MS based on proteomic and ELISA assays.Key Results: Functional and docking analyses showed that Δ9-THCA-A can act as anorthosteric CB1 receptor agonist and also as a positive allosteric modulator in thepresence of CP-55,940. Also, Δ9-THCA-A seemed to be an inverse agonist for CB2receptors. In vivo, Δ9-THCA-A reduced arthritis in CIA mice, preventing the infiltra tion 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 orT0070907. Analysis of plasma biomarkers, and determination of cytokines and anti collagen antibodies confirmed that Δ9-THCA-A mediated its activity mainly throughPPARγ and CB1 receptor pathways.Conclusion and Implications: Δ9-THCA-A modulates CB1 receptors through theorthosteric and allosteric binding sites. In addition, Δ9-THCA-A exerts anti-arthritisactivity through CB1 receptors and PPARγ pathways, highlighting its potential for thetreatment of chronic inflammatory diseases such as rheumatoid arthritis.
PB Br J Pharmacol
SN 0007-1188
SN 1476-5381
YR 2020
FD 2020-07-08
LK https://hdl.handle.net/20.500.14352/93324
UL https://hdl.handle.net/20.500.14352/93324
LA eng
NO Palomares B, Garrido-Rodríguez M, Gonzalo-Consuegra C, Gómez-Cañas M, Saen-oon S, Soliva R, Collado JA, Fernández-Ruiz J, Morello G, Calzado MA, Appendino G, Muñoz E. Δ9‐tetrahydrocannabinolic acid alleviates collagen‐induced arthritis: role of PPARγ and CB1 receptors. Br J Pharmacol. 2020, 177(17):4034-4054.
NO Instituto de Salud Carlos III
NO Centre for Industrial Technological Development
NO Universidad Complutense de Madrid
NO Fundación Marcelino Botín
NO Ministerio de Ciencia e Innovación
NO Secretaría de Estado de Investigación, Desarrolloe Innovación
DS Docta Complutense
RD 7 abr 2025