Dataset Information

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 | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Δ<sup>9</sup> -Tetrahydrocannabinolic acid alleviates collagen-induced arthritis: Role of PPARγ and CB<sub>1</sub> receptors.

Palomares Belén B Garrido-Rodriguez Martín M Gonzalo-Consuegra Claudia C Gómez-Cañas María M Saen-Oon Suwipa S Soliva Robert R Collado Juan A JA Fernández-Ruiz Javier J Morello Gaetano G Calzado Marco A MA Appendino Giovanni G Muñoz Eduardo E

British journal of pharmacology 20200708 17

<h4>Background and purpose</h4>Δ<sup>9</sup> -Tetrahydrocannabinolic acid (Δ<sup>9</sup> -THCA-A), the precursor of Δ<sup>9</sup> -THC, is a non-psychotropic phytocannabinoid that shows PPARγ agonist activity. Here, we investigated the ability of Δ<sup>9</sup> -THCA-A to modulate the classic cannabinoid CB<sub>1</sub> and CB<sub>2</sub> receptors and evaluated its anti-arthritis activity in vitro and in vivo.<h4>Experimental approach</h4>Cannabinoid receptors binding and intrinsic activity, as w ...[more]

PMID: 32510591

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Project description:Introduction: Compounds present in Cannabis sativa such as phytocannabinoids and terpenoids may act in concert to elicit therapeutic effects. Cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) directly activate cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2); however, it is not known if terpenoids present in Cannabis also affect cannabinoid receptor signaling. Therefore, we examined six common terpenoids alone, and in combination with cannabinoid receptor agonists, on CB1 and CB2 signaling in vitro. Materials and Methods: Potassium channel activity in AtT20 FlpIn cells transfected with human CB1 or CB2 receptors was measured in real time using FLIPR® membrane potential dye in a FlexStation 3 plate reader. Terpenoids were tested individually and in combination for periods up to 30 min. Endogenous somatostatin receptors served as a control for direct effects of drugs on potassium channels. Results: α-Pinene, β-pinene, β-caryophyllene, linalool, limonene, and β-myrcene (up to 30-100 μM) did not change membrane potential in AtT20 cells expressing CB1 or CB2, or affect the response to a maximally effective concentration of the synthetic cannabinoid CP55,940. The presence of individual or a combination of terpenoids did not affect the hyperpolarization produced by Δ9-THC (10 μM): (CB1: control, 59%±7%; with terpenoids (10 μM each) 55%±4%; CB2: Δ9-THC 16%±5%, with terpenoids (10 μM each) 17%±4%). To investigate possible effect on desensitization of CB1 responses, all six terpenoids were added together with Δ9-THC and signaling measured continuously over 30 min. Terpenoids did not affect desensitization, after 30 min the control hyperpolarization recovered by 63%±6% in the presence of the terpenoids recovery was 61%±5%. Discussion: None of the six of the most common terpenoids in Cannabis directly activated CB1 or CB2, or modulated the signaling of the phytocannabinoid agonist Δ9-THC. These results suggest that if a phytocannabinoid-terpenoid entourage effect exists, it is not at the CB1 or CB2 receptor level. It remains possible that terpenoids activate CB1 and CB2 signaling pathways that do not involve potassium channels; however, it seems more likely that they may act at different molecular target(s) in the neuronal circuits important for the behavioral effect of Cannabis.

Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Δ<sup>9</sup> -Tetrahydrocannabinolic acid alleviates collagen-induced arthritis: Role of PPARγ and CB<sub>1</sub> receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Δ<sup>9</sup> -Tetrahydrocannabinolic acid alleviates collagen-induced arthritis: Role of PPARγ and CB<sub>1</sub> receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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