Δ⁹ -Tetrahydrocannabinolic acid alleviates collagen-induced arthritis: Role of PPARγ and CB₁ receptors.

ABSTRACT:

Background and purpose

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.

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 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.

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.

SUBMITTER: Palomares B 

PROVIDER: S-EPMC7429492 | biostudies-literature |

REPOSITORIES: biostudies-literature