Delta(9)-Tetrahydrocannabinolic acid alleviates collagen-induced arthritis: Role of PPAR gamma and CB(1)receptors

Background and Purpose Delta(9)-Tetrahydrocannabinolic acid (Delta(9)-THCA-A), the precursor of Delta(9)-THC, is a non-psychotropic phytocannabinoid that shows PPAR gamma agonist activity. Here, we investigated the ability of Delta(9)-THCA-A to modulate the classic cannabinoid CB(1)and CB(2)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 Delta(9)-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 andelisaassays. Key Results Functional and docking analyses showed that Delta(9)-THCA-A can act as an orthosteric CB(1)receptor agonist and also as a positive allosteric modulator in the presence of CP-55,940. Also, Delta(9)-THCA-A seemed to be an inverse agonist for CB(2)receptors. In vivo, Delta(9)-THCA-A reduced arthritis in CIA mice, preventing the infiltration of inflammatory cells, synovium hyperplasia, and cartilage damage. Furthermore, Delta(9)-THCA-A inhibited expression of inflammatory and catabolic genes on knee joints. The anti-arthritic effect of Delta(9)-THCA-A was blocked by either SR141716 or T0070907. Analysis of plasma biomarkers, and determination of cytokines and anti-collagen antibodies confirmed that Delta(9)-THCA-A mediated its activity mainly through PPAR gamma and CB(1)receptor pathways. Conclusion and Implications Delta(9)-THCA-A modulates CB(1)receptors through the orthosteric and allosteric binding sites. In addition, Delta(9)-THCA-A exerts anti-arthritis activity through CB(1)receptors and PPAR gamma pathways, highlighting its potential for the treatment of chronic inflammatory diseases such as rheumatoid arthritis.