Identification and characterization of phytocannabinoids as novel dual PPARα/γ agonists by a computational and in vitro experimental approach

D’Aniello, Enrico; Fellous, Tariq G.; Iannotti, Fabio Arturo; Gentile, Alessandra; Allarà, Marco; Balestrieri, Francesca; Gray, Roy; Amodeo, Pietro; Vitale, Rosa; Marzo, Vincenzo Di

doi:10.1016/j.bbagen.2019.01.002

Cited by 61 publications

(47 citation statements)

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“…TRP channels detect physical and chemical stimuli and promote painful sensations via nociceptor activation (Marwaha et al, ) and the stimulating effects of cannabinoids at TRPV1 may lead to desensitization of this channel (Morita et al, ; Ursu, Knopp, Beattie, Liu, & Sher, ). Furthermore, CBDA has been shown, by computational modelling and cell culture‐based experiments, to act as a dual PPAR‐α and PPAR‐γ agonist (D'Aniello et al, ). A recent study demonstrated a link between dual PPARα/γ activation and TRPV1 in two different models of rat neuropathic pain (Alsalem et al, ).…”

Section: Discussionmentioning

confidence: 99%

An evaluation of the anti‐hyperalgesic effects of cannabidiolic acid‐methyl ester in a preclinical model of peripheral neuropathic pain

Zhu

Linher‐Melville

Niazmand

et al. 2020

British J Pharmacology

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Background and Purpose: Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable.Experimental Approach: After 14 consecutive days of intraperitoneal CBDA-ME administration at 0.01, 0.1 and 1 μgÁkg −1 , commencing 1 day after surgically implanting a sciatic nerve-constricting cuff to induce NEP, the anti-nociceptive efficacy of this cannabinoid was assessed in male and female Sprague-Dawley rats relative to vehicle-treated counterparts. In females, 2 and 4 μgÁkg −1 daily doses of CBDA-ME were also evaluated. Behavioural tests were performed for hind paw mechanical and thermal withdrawal thresholds once a week for 8 weeks. At endpoint, in vivo electrophysiological recordings were obtained to characterize soma threshold changes in primary sensory neurons. Key Results:In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and nonnociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested. Conclusion and Implications:Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response.

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Section: Discussionmentioning

confidence: 99%

An evaluation of the anti‐hyperalgesic effects of cannabidiolic acid‐methyl ester in a preclinical model of peripheral neuropathic pain

Zhu

Linher‐Melville

Niazmand

et al. 2020

British J Pharmacology

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“…Phytocannabinoids (pCBs) are a class of secondary metabolites isolated from C. sativa, counting more than 100 compounds with a still largely unexplored pharmacological potential [16]. THC and CBD, the most representative pCBs, have interesting therapeutic applications due to their complex pharmacological profile, and they are active on the PPARγ receptor, while a few other neutral and acidic pCBs were characterized as dual PPARα/γ agonists [15]. Due to its role in adipocyte differentiation, lipid metabolism, glucose homeostasis, insulin sensitivity, and, more recently, in inflammatory and immune responses, PPARγ represents an attractive pharmacological target to address metabolic disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Due to its role in adipocyte differentiation, lipid metabolism, glucose homeostasis, insulin sensitivity, and, more recently, in inflammatory and immune responses, PPARγ represents an attractive pharmacological target to address metabolic disorders. As part of our discovery program on nuclear receptor ligands from marine [24,25] and terrestrial sources [15], we focused on cannabimovone (CBM), a polar pCB characterized by a unique abeo-menthane terpenyl moiety isolated in 2010 from a non-psychotropic variety of C. sativa (Italian cultivar Carmagnola) [17]. The chemical structure of cannabimovone, including stereochemical details, was recently confirmed by total synthesis, which can also be considered as an alternative to the exploitation of the natural source [26].…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Cannabimovone, a Cannabinoid from Cannabis sativa, as a Novel PPARγ Agonist via a Combined Computational and Functional Study

et al. 2020

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Phytocannabinoids (pCBs) are a large family of meroterpenoids isolated from the plant Cannabis sativa. Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best investigated phytocannabinoids due to their relative abundance and interesting bioactivity profiles. In addition to various targets, THC and CBD are also well-known agonists of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor involved in energy homeostasis and lipid metabolism. In the search of new pCBs potentially acting as PPARγ agonists, we identified cannabimovone (CBM), a structurally unique abeo-menthane pCB, as a novel PPARγ modulator via a combined computational and experimental approach. The ability of CBM to act as dual PPARγ/α agonist was also evaluated. Computational studies suggested a different binding mode toward the two isoforms, with the compound able to recapitulate the pattern of H-bonds of a canonical agonist only in the case of PPARγ. Luciferase assays confirmed the computational results, showing a selective activation of PPARγ by CBM in the low micromolar range. CBM promoted the expression of PPARγ target genes regulating the adipocyte differentiation and prevented palmitate-induced insulin signaling impairment. Altogether, these results candidate CBM as a novel bioactive compound potentially useful for the treatment of insulin resistance-related disorders.

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“…In the biochemical analysis, we assayed CBDA as an anti-inflammatory candidate as it has been found to exert such effects in vitro [4,5] and in vivo [19]. Furthermore, CBDA exerts agonistic effects on TRPV1 [10,11] and PPARγ [12,13], which are tightly related to inflammatory processes. Therefore, we measured IL-6 and PPARγ protein levels in PFC, a brain area constitutively engaged in evaluated phenomena, such as cognition, emotion, nociception and motivation [27].…”

Section: Discusionmentioning

confidence: 99%

“…Additionally, CBDA could act as an enhancer of the receptor of serotonin 1A (5-HT 1A ) activation [7][8][9], an agonist of the transient receptor potential cation channel vanilloid 1 (TRPV1) and transient receptor potential cation channel ankyrin 1 (TRPA1), and an antagonist of transient receptor potential cation channel melastatin 8 (TRPM8) revealed by in vitro assays [10,11]. Recently, CBDA has been found to act as a dual proliferator-activated receptor (PPAR) α/γ agonist in computational [12] and in vitro [12,13] cell culture experimental approaches, including mouse and human brain cells.…”

Section: Introductionmentioning

confidence: 99%

Behavioural and Molecular Effects of Cannabidiolic Acid in Mice

Alegre-Zurano

Martín‐Sánchez

Valverde

2020

Preprint

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Aims: Cannabidiolic acid (CBDA) is one of the most abundant phytocannabinoid acids in the Cannabis Sativa plant. It has been shown it is able to exert some therapeutic effects such as antiemetic, anti-inflammatory, anxiolytic or antidepressant, although some of them remain under debate. In the present study we aim to assess the potential effects of CBDA on different behaviours and on the modulation of neuroinflammatory markers in the prefrontal cortex (PFC).Main methods: the effects of acute and/or chronic CBDA (0.001-1 mg/kg i.p.) treatment were evaluated on cognitive, emotional, motivational and nociceptive behaviours in male CD1 mice. For this, Y-maze and elevated plus maze paradigms, spontaneous locomotor activity, social interaction, hot-plate, formalin and tail suspension tests were used. We also studied the effects of CBDA on the rewarding responses of cocaine in the conditioned place preference (CPP) paradigm. PFC was dissected after acute and chronic CBDA treatments to evaluate inflammatory markers.Key findings: acute CBDA treatment induced antinociceptive responses in the hot-plate test. A 10-day chronic CBDA treatment reduced despair-like behaviour in the tail suspension test. CBDA did not alter the remaining behavioural tests assayed, including cocaine-induced reward in the CPP. Regarding the biochemical analysis, chronic CBDA treatment diminished peroxisome proliferator-activated receptor gamma (PPAR-γ) and increased interleukin-6 (IL-6) protein levels in PFC.Significance: these results show that CBDA has limited in vivo effects modulating mice behaviour, highlighting the current disagreement regarding its therapeutic potential.

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Identification and characterization of phytocannabinoids as novel dual PPARα/γ agonists by a computational and in vitro experimental approach

Cited by 61 publications

References 50 publications

An evaluation of the anti‐hyperalgesic effects of cannabidiolic acid‐methyl ester in a preclinical model of peripheral neuropathic pain

An evaluation of the anti‐hyperalgesic effects of cannabidiolic acid‐methyl ester in a preclinical model of peripheral neuropathic pain

Identification and Characterization of Cannabimovone, a Cannabinoid from Cannabis sativa, as a Novel PPARγ Agonist via a Combined Computational and Functional Study

Behavioural and Molecular Effects of Cannabidiolic Acid in Mice

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