Δ9-TETRAHYDROCANNABINOLIC ACID ALLEVIATES COLLAGEN-INDUCED ARTHRITIS: ROLE OF PPARγ AND CB 1 RECEPTORS

Background and purpose: Δ⁹ -THCA-A, the precursor of Δ⁹ -THC, is a non-psychotropic phytocannabinoid that shows PPARγ agonistic activity. Herein, we investigated Δ⁹ -THCA ability to modulate classic cannabinoid receptors (CB₁ and CB₂ ) and evaluated its anti-arthritis activity.

Experimental approach: Cannabinoid receptors binding and intrinsic activity, as well as their downstream signaling were analyzed 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). Plasmatic disease biomarkers were identified by liquid chromatography-tandem mass spectrometry (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 agonist and also as a positive allosteric modulator in the presence of CP-55,940. In addition, Δ⁹ -THCA-A seemed to be an inverse agonist for CB_2. In vivo experiments showed that Δ⁹ -THCA-A reduced arthritis in CIA mice. Δ⁹ -THCA-A prevented the infiltration of inflammatory cells; synovium hyperplasia and cartilage damage. Furthermore, Δ⁹ -THCA-A inhibited the expression of inflammatory and catabolic genes on knee joints. The anti-arthritic effect of Δ⁹ -THCA-A was ablated by either SR141716 or T0070907. Analysis of plasmatic biomarkers as well as determination of cytokines and anti-collagen antibodies confirmed that Δ⁹ -THCA-A mediates its activity mainly through PPARγ and CB₁ pathways.

Conclusion and implications: Δ⁹ -THCA-A modulates CB₁ receptor through the orthosteric and allosteric binding sites. In addition, our studies document that Δ⁹ -THCA-A exerts anti-arthritis activity through CB₁ /PPARγ pathways, highlighting its potential for the treatment of chronic inflammatory diseases such as Rheumatoid Arthritis (RA).