RT Journal Article
T1 Δ9 -Tetrahydrocannabinolic acid alleviates collagen-induced arthritis: Role of PPARγ and CB1 receptors.
A1 Palomares, Belen
A1 Garrido-Rodriguez, Martin
A1 Gonzalo-Consuegra, Claudia
A1 Gomez-Cañas, Maria
A1 Saen-Oon, Suwipa
A1 Soliva, Robert
A1 Collado, Juan A
A1 Fernandez-Ruiz, Javier
A1 Morello, Gaetano
A1 Calzado, Marco A
A1 Appendino, Giovanni
A1 Muñoz, Eduardo
K1 PPAR gamma
K1 Proteomics
K1 Receptor, Cannabinoid, CB1
K1 Receptor, Cannabinoid, CB2
K1 Tandem Mass Spectrometry
AB 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. 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. 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. 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.
PB John Wiley & Sons
YR 2020
FD 2020-05-27
LK http://hdl.handle.net/10668/15696
UL http://hdl.handle.net/10668/15696
LA en
NO Palomares B, Garrido-Rodriguez M, Gonzalo-Consuegra C, Gómez-Cañas M, Saen-Oon S, Soliva R, et al. Δ9 -Tetrahydrocannabinolic acid alleviates collagen-induced arthritis: Role of PPARγ and CB1 receptors. Br J Pharmacol. 2020 Sep;177(17):4034-4054
DS RISalud
RD Apr 5, 2025