Abstract
Cannabinoids have shown to exert their therapeutic actions through a variety of targets. These include not only the canonical cannabinoid receptors CB1R and CB2R but also related orphan G protein-coupled receptors (GPCRs), ligand-gated ion channels, transient receptor potential (TRP) channels, metabolic enzymes, and nuclear receptors. In this review, we aim to summarize reported compounds exhibiting their therapeutic effects upon the modulation of CB1R and/or CB2R and the nuclear peroxisome proliferator-activated receptors (PPARs). Concomitant actions at CBRs and PPARα or PPARγ subtypes have shown to mediate antiobesity, analgesic, antitumoral, or neuroprotective properties of a variety of phytogenic, endogenous, and synthetic cannabinoids. The relevance of this multitargeting mechanism of action has been analyzed in the context of diverse pathologies. Synergistic effects triggered by combinatorial treatment with ligands that modulate the aforementioned targets have also been considered. This literature overview provides structural and pharmacological insights for the further development of dual cannabinoids for specific disorders.
Highlights
Was effective in nicotine reward and withdrawal [110], and this effect was proposed to be mediated by PPARα rather than fatty acid amide hydrolase (FAAH)
This was based on the fact that in a nicotine-dependent mice-conditioned place preference paradigm, the peroxisome proliferator-activated receptors (PPARs)-α antagonist GW6471 prevented the effect of oleoyl glycine (OlGly), whereas the lack of activity at FAAH was based on in vitro luciferase assays in which OlGly showed low agonism [110]
In the context of a dual PPAR/cannabinoid receptors (CBRs) strategy, it is worth mentioning the randomized, placebo-controlled, double-blind controlled trial realized on healthy human subjects in which a state of increased gut permeability was induced by aspirin [124]
Summary
Muchmade progress in the of the ECS has been knowledge made in theofpast years This includes a better knowledge of the signaling mechanisms and structural features of network involved in (CBRs) endocannabinoid metabolism, and the discovery of other G cannabinoid receptors [13], the mediator network involved in endocannabinoid protein-coupled receptors (GPCRs), channels, and nuclear for metabolism, and the discovery of otherion. Three subtypes have been identified: PPARα, PPARβ/δ, and PPARγ [37] They are ligand-dependent transcription factors that regulate target gene expression by binding to specific peroxisome proliferator response elements (PPREs). CBRs and PPARs have shown to exhibit biological relevance in common pathophysiological contexts Both CB1 R and PPARα have shown a therapeutic role in the regulation of lipid metabolism. We will explore the connection between PPARs and elements of the ECS through the action of different cannabinoids reported so far to be engaged in this relationship
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