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.

Evaluation of the Possible Anticonvulsant Effect of Δ9-Tetrahydrocannabinolic Acid in Murine Seizure Models

“…Recently, Δ 9 -THCA was reported to be a positive allosteric modulator of CB 1 receptors. 30 Alternatively, our observation that Δ 9 -THCA increased plasma concentrations of Δ 9 -THC points to a pharmacokinetic interaction that could be explored in future studies.…”

Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System

“…These effects were abolished upon treatment with either SR141716 or T0070907 (PPARγ antagonist). THCA direct activation of both CB 1 R and PPARγ was confirmed by competitive binding assays and functional studies [81,82]. At CB 1 R, it was shown to act as an orthosteric agonist or as a positive allosteric modulator in the presence of the synthetic agonist CP-55,940 [81].…”

“…THCA direct activation of both CB 1 R and PPARγ was confirmed by competitive binding assays and functional studies [81,82]. At CB 1 R, it was shown to act as an orthosteric agonist or as a positive allosteric modulator in the presence of the synthetic agonist CP-55,940 [81]. It also behaves as a CB 2 R inverse agonist; however, this effect was not involved in ∆ 9 -THCA anti-arthritis properties.…”

“…The role of CB 1 R and PPARγ has also been extensively demonstrated in inflammatory processes [78][79][80]. Indeed, ∆ 9tetrahydrocannabinolic acid (THCA), a phytogenic precursor of THC, exerts anti-arthritis activity through CB 1 R and PPARγ pathways [81]. In a murine model of collagen-induced arthritis, THCA was able to significantly decrease inflammatory biomarkers, synovial hyperplasia, and cartilage damage.…”

Endocannabinoid System Receptors at the Hip and Stifle Joints of Middle-Aged Dogs: A Novel Target for the Therapeutic Use of Cannabis sativa Extract in Canine Arthropathies

“…Recent studies have shown that the activation of CB1R by minor phytocannabinoids exerts anti-arthritis activity in murine models, highlighting its potential for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) [ 12 ]. Similarly, CB2R pharmacological activation in a mouse model of osteoarthritis (OA) showed a protective effect, indicating the potential role of CB2R in the pathogenesis of the disease [ 13 ].…”