Δ ⁹ ‐Tetrahydrocannabinolic acid alleviates collagen‐induced arthritis: Role of PPARγ and CB ₁ receptors

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