Abstract Objective Extreme obesity is a core phenotypic feature of Prader–Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in ...controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1 R) blockade reverses obesity both in animals and humans. The first-in-class CB1 R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. Methods We studied eCB ‘tone’ in individuals with PWS and in the Magel2 -null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1 R antagonist, JD5037 in treating obesity in these mice. Results Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB ‘tone’, manifested by increased eCBs and upregulated CB1 R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2 -null mice. Daily chronic treatment of obese Magel2 -null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days) reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. Conclusions Dysregulation of the eCB/CB1 R system may contribute to hyperphagia and obesity in Magel2 -null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1 R antagonists may be an effective strategy for the management of severe obesity in PWS.
Molecular interactions between anorexigenic leptin and orexigenic endocannabinoids, although of great metabolic significance, are not well understood. We report here that hypothalamic STAT3 signaling ...in mice, initiated by physiological elevations of leptin, is diminished by agonists of the cannabinoid receptor 1 (CB1R). Measurement of STAT3 activation by semi-automated confocal microscopy in cultured neurons revealed that this CB1R-mediated inhibition requires both T cell protein tyrosine phosphatase (TC-PTP) and β-arrestin1 but is independent of changes in cAMP. Moreover, β-arrestin1 translocates to the nucleus upon CB1R activation and binds both STAT3 and TC-PTP. Consistently, CB1R activation failed to suppress leptin signaling in β-arrestin1 knockout mice in vivo, and in neural cells deficient in CB1R, β-arrestin1 or TC-PTP. Altogether, CB1R activation engages β-arrestin1 to coordinate the TC-PTP-mediated inhibition of the leptin-evoked neuronal STAT3 response. This mechanism may restrict the anorexigenic effects of leptin when hypothalamic endocannabinoid levels rise, as during fasting or in diet-induced obesity.
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•Leptin-induced STAT3 phosphorylation is attenuated by CB1 receptor agonists•Upon CB1 and leptin receptor co-stimulation β-arrestin1 translocates to the nucleus•β-arrestin1 binds STAT3 and the nuclear phosphotyrosine phosphatase TC-PTP•TC-PTP then dephosphorylates STAT3
Molecular biology; Cell biology
Hermansky–Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS‐1, leads to fatal adult‐onset pulmonary fibrosis (PF) with no effective treatment. We ...evaluated the role of the endocannabinoid/CB1R system and inducible nitric oxide synthase (iNOS) for dual‐target therapeutic strategy using human bronchoalveolar lavage fluid (BALF), lung samples from patients with HPS and controls, HPS‐PF patient‐derived lung fibroblasts, and bleomycin‐induced PF in pale ear mice (HPS1ep/ep). We found overexpression of CB1R and iNOS in fibrotic lungs of HPSPF patients and bleomycin‐infused pale ear mice. The endocannabinoid anandamide was elevated in BALF and negatively correlated with pulmonary function parameters in HPSPF patients and pale ear mice with bleomycin‐induced PF. Simultaneous targeting of CB1R and iNOS by MRI‐1867 yielded greater antifibrotic efficacy than inhibiting either target alone by attenuating critical pathologic pathways. Moreover, MRI‐1867 treatment abrogated bleomycin‐induced increases in lung levels of the profibrotic interleukin‐11 via iNOS inhibition and reversed mitochondrial dysfunction via CB1R inhibition. Dual inhibition of CB1R and iNOS is an effective antifibrotic strategy for HPSPF.
Overactivity of CB1R and iNOS contributes to HPSPF development and progression via multiple critical pathological processes including dysregulation of mitochondrial function and IL‐11. Simultaneous inhibition of lung CB1R and iNOS by a hybrid inhibitor (MRI‐1867) is a rational therapeutic strategy for achieving therapeutic efficacy in HPSPF with attenuating fibrosis, improving pulmonary function and survival.
Aberrant fibroblast function plays a key role in the pathogenesis of idiopathic pulmonary fibrosis, a devastating disease of unrelenting extracellular matrix deposition in response to lung injury. ...Platelet-derived growth factor α-positive (Pdgfra+) lipofibroblasts (LipoFBs) are essential for lung injury response and maintenance of a functional alveolar stem cell niche. Little is known about the effects of lung injury on LipoFB function. Here, we used single-cell RNA-Seq (scRNA-Seq) technology and PdgfraGFP lineage tracing to generate a transcriptomic profile of Pdgfra+ fibroblasts in normal and injured mouse lungs 14 days after bleomycin exposure, generating 11 unique transcriptomic clusters that segregated according to treatment. While normal and injured LipoFBs shared a common gene signature, injured LipoFBs acquired fibrogenic pathway activity with an attenuation of lipogenic pathways. In a 3D organoid model, injured Pdgfra+ fibroblast-supported organoids were morphologically distinct from those cultured with normal fibroblasts, and scRNA-Seq analysis suggested distinct transcriptomic changes in alveolar epithelia supported by injured Pdgfra+ fibroblasts. In summary, while LipoFBs in injured lung have not migrated from their niche and retain their lipogenic identity, they acquire a potentially reversible fibrogenic profile, which may alter the kinetics of epithelial regeneration and potentially contribute to dysregulated repair, leading to fibrosis.
The aim of this study was to evaluate the feasibility of targeted imaging of myocardial cannabinoid type 1 receptor (CB1-R) and its potential up-regulation in obese mice with translation to humans ...using 11C-OMAR and positron emission tomography (PET)/computed tomography (CT).
Activation of myocardial CB1-R by endocannabinoids has been implicated in cardiac dysfunction in diabetic mice. Obesity may lead to an up-regulation of myocardial CB1-R, potentially providing a mechanistic link between obesity and the initiation and/or progression of cardiomyopathy.
Binding specificity of 11C-OMAR to CB1-R was investigated by blocking studies with rimonabant in mice. The heart was harvested from each mouse, and its radioactivity was determined by γ-counter. Furthermore, 11C-OMAR dynamic micro-PET/CT was carried out in obese and normal-weight mice. Ex vivo validation was performed by droplet digital polymerase chain reaction (absolute quantification) and RNAscope Technology (an in situ ribonucleic acid analysis platform). Subsequently, myocardial CB1-R expression was probed noninvasively with intravenous injection of CB1-R ligand 11C-OMAR and PET/CT in humans with advanced obesity and normal-weight human control subjects, respectively.
Rimonabant significantly blocked OMAR uptake in the heart muscle compared with vehicle, signifying specific binding of OMAR to the CB1-R in the myocardium. The myocardial OMAR retention quantified by micro-PET/CT in mice was significantly higher in obese compared with normal-weight mice. Absolute quantification of CB1-R gene expression with droplet digital polymerase chain reaction and in situ hybridization confirmed CB1-R up-regulation in all major myocardial cell types (e.g., cardiomyocytes, endothelium, vascular smooth muscle cells, and fibroblasts) of obese mice. Obese mice also had elevated myocardial levels of endocannabinoids anandamide and 2-arachidonoylglycerol compared with lean mice. Translation to humans revealed higher myocardial OMAR retention in advanced obesity compared with normal-weight subjects.
Noninvasive imaging of cardiac CB1-R expression in obesity is feasible applying 11C-OMAR and PET/CT. These results may provide a rationale for further clinical testing of CB1-R-targeted molecular imaging in cardiometabolic diseases.
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COVID‐19 (SARS‐CoV‐2) causes multiple inflammatory complications, resulting not only in severe lung inflammation but also harm to other organs. Although the current focus is on the management of ...acute COVID‐19, there is growing concern about long‐term effects of COVID‐19 (Long Covid), such as fibroproliferative changes in the lung, heart and kidney. Therefore, the identification of therapeutic targets not only for the management of acute COVID‐19 but also for preventing Long Covid are needed, and would mitigate against long‐lasting health burden and economic costs, in addition to saving lives. COVID‐19 induces pathological changes via multiple pathways, which could be targeted simultaneously for optimal effect. We discuss the potential pathologic function of increased activity of the endocannabinoid/CB1 receptor system and inducible NO synthase (iNOS). We advocate a polypharmacology approach, wherein a single chemical entity simultaneously interacts with CB1 receptors and iNOS causing inhibition, as a potential therapeutic strategy for COVID‐19‐related health complications.
LINKED ARTICLES
This article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetoc
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•Alcohol is one of the most frequently used intoxicants in the United States. Binge alcohol drinking is a major contributor of emergency department visits.•Binge alcohol drinking may ...adversely affect cardiovascular function.•Here we show that acute alcohol intoxication is associated with elevated levels of cardiac endocannabinoid anandamide and profound cardiovascular dysfunction and blood redistribution lasting for several hours.•The adverse cardiovascular effects of acute alcohol intoxication are attenuated by CB1-R antagonist or in CB1-R knockout mice.•A single alcohol binge has profound effect on the cardiovascular system, which involves endocannabinoid-CB1-R signaling.
Excessive binge alcohol drinking may adversely affect cardiovascular function. In this study we characterize the detailed hemodynamic effects of an acute alcohol binge in mice using multiple approaches and investigate the role of the endocannabinoid–cannabinoid 1 receptor (CB1-R) signaling in these effects. Acute alcohol binge was associated with elevated levels of cardiac endocannabinoid anandamide and profound cardiovascular dysfunction lasting for several hours and redistribution of circulation. These changes were attenuated by CB1-R antagonist or in CB1-R knockout mice. Our results suggest that a single alcohol binge has profound effects on the cardiovascular system, which involve endocannabinoid–CB1-R signaling.
Here we have studied regulatory changes of µ-opioid receptors accompanying in vivo 14-methoxymetopon treatments of rats. Previously, this ligand has been shown to be an extremely potent, centrally ...acting µ-opioid specific analgesic with low physical dependence, tolerance, respiratory depression, constipation and other side effects. Our work shows that it is a highly potent full agonist of µ-opioid receptor coupled G-protein signaling in vitro, alike the well-known opioid agonist, etorphine. However, unlike etorphine, which desensitized and down-regulated the endogenous µ-opioid receptors, 14-methoxymetopon, given to rats intraperitoneally (i.p.) either acutely or chronically, did not change the binding or G-protein signaling of µ-opioid receptors in rat brain subcellular membranes. Thereby, these data provide further evidence that there is no direct relationship between the efficacy of the ligand in signaling and its ability to internalize or desensitize the receptor. Viewed collectively with published work, it is discussed that µ-opioid receptors display functional selectivity, also called 'biased agonism'. This concept implies that each ligand may induce unique, ligand-specific receptor conformation that can result in distinct agonist- directed trafficking and/or signal transduction pathways associated with the receptor. Ligand-specific signaling may open up new directions for designing potent analgesics that do not interact with unwanted signaling pathways, which mediate undesired side-effects, such as tolerance and dependence.
•Endocannabinoid system induces dual effects in epilepsy.•Endocannabinoids can induce neuroinflammation and neurotoxicity.•The effects of endocannabinoids can depend on the pathological ...microenvironment.
Epilepsy is a neurological disorder with a high prevalence worldwide. Several studies carried out during the last decades indicate that the administration of cannabinoids as well as the activation of the endocannabinoid system (ECS) represent a therapeutic strategy to control epilepsy. However, there are controversial studies indicating that activation of ECS results in cell damage, inflammation and neurotoxicity, conditions that facilitate the seizure activity. The present review is focused to present findings supporting this issue. According to the current discrepancies, it is relevant to elucidate the different effects induced by the activation of ECS and determine the conditions under which it facilitates the seizure activity.
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