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oai:docta.ucm.es:20.500.14352/933242024-01-17T02:32:28Zcom_20.500.14352_14col_20.500.14352_15

Δ9‐Tetrahydrocannabinolic acid alleviates collagen‐induced arthritis: Role of PPARγ and CB1 receptors Palomares, Belén Gonzalo Consuegra, Claudia Gómez Cañas, María Fernández Ruiz, José Javier Muñoz, Eduardo 577.2 Ciencias Biomédicas 24 Ciencias de la Vida Background and Purpose: Δ9 -Tetrahydrocannabinolic acid (Δ9 -THCA-A), the precur sor 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 can nabinoid 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 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 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. Instituto de Salud Carlos III Centre for Industrial Technological Development Universidad Complutense de Madrid Fundación Marcelino Botín Ministerio de Ciencia e Innovación Secretaría de Estado de Investigación, Desarrolloe Innovación Depto. de Bioquímica y Biología Molecular Fac. de Medicina TRUE pub 2024-01-16T11:13:43Z 2024-01-16T11:13:43Z 2020-07-08 journal article VoR https://hdl.handle.net/20.500.14352/93324 0007-1188 1476-5381 10.1111/bph.15155 eng IFI15/00022 00094141/SNEO-20161127 RTI2018-098885-B-100 SAF2017-87701-R 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. Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ open access application/pdf Br J Pharmacol