Background and purpose:
Accumulating recent evidence suggests that cannabinoid‐1 (CB
1
) receptor activation may promote inflammation and cell death and its pharmacological inhibition is associated ...with anti‐inflammatory and tissue‐protective effects in various preclinical disease models, as well as in humans.
Experimental approach:
In this study, using molecular biology and biochemistry methods, we have investigated the effects of genetic deletion or pharmacological inhibition of CB
1
receptors on inflammation, oxidative/nitrosative stress and cell death pathways associated with a clinically relevant model of nephropathy, induced by an important chemotherapeutic drug cisplatin.
Results:
Cisplatin significantly increased endocannabinoid anandamide content, activation of p38 and JNK mitogen‐activated protein kinases (MAPKs), apoptotic and poly (ADP‐ribose)polymerase‐dependent cell death, enhanced inflammation (leucocyte infiltration, tumour necrosis factor‐α and interleukin‐1β) and promoted oxidative/nitrosative stress increased expressions of superoxide‐generating enzymes (NOX2(gp91phox), NOX4), inducible nitric oxide synthase and tissue 4‐hydroxynonenal and nitrotyrosine levels in the kidneys of mice, accompanied by marked histopathological damage and impaired renal function (elevated creatinine and serum blood urea nitrogen) 3 days following its administration. Both genetic deletion and pharmacological inhibition of CB
1
receptors with AM281 or SR141716 markedly attenuated the cisplatin‐induced renal dysfunction and interrelated oxidative/nitrosative stress, p38 and JNK MAPK activation, cell death and inflammatory response in the kidney.
Conclusions and implications:
The endocannabinoid system through CB
1
receptors promotes cisplatin‐induced tissue injury by amplifying MAPK activation, cell death and interrelated inflammation and oxidative/nitrosative stress. These results also suggest that inhibition of CB
1
receptors may exert beneficial effects in renal (and most likely other) diseases associated with enhanced inflammation, oxidative/nitrosative stress and cell death.
This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit
http://dx.doi.org/10.1111/j.1476‐5381.2010.00831.x
Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, ...and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with Gi, as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.
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•3D structures of CB2-AM12033-Gi, CB1-AM841-Gi, and CB2-AM12033 are determined•Structural evidence of G protein selectivity by CB1 and CB2 is identified•MD simulations reveal the distinct binding behavior of HU308 in CB2 and CB1•Cholesterol molecule as an endogenous allosteric modulator of CB1 is uncovered
Structure and simulations of cannabinoid receptors CB2 and CB1 in their inactive, active-like, and activated signaling states reveal residue differences that may provide G protein selectivity, the distinct binding behavior of CB2 agonists in CB2 and CB1, as well as evidence for modulation of CB1 by cholesterol binding.
Endocannabinoids are lipid mediators that interact with the same cannabinoid receptors that recognize Δ9‐tetrahydrocannabinol (THC), the psychoactive constituent of marijuana, to induce similar ...effects in the brain and periphery. Alcohol and THC are both addictive substances whose acute use elicits rewarding effects that can lead to chronic and compulsive use via engaging similar signaling pathways in the brain. In the liver, both alcohol and endocannabinoids activate lipogenic gene expression leading to fatty liver disease. This review focuses on evidence accumulated over the last 2 decades to indicate that both the addictive neural effects of ethanol and its organ toxic effects in the liver and elsewhere are mediated, to a large extent, by endocannabinoids signaling via cannabinoid‐1 receptors (CB1R). The therapeutic potential of CB1R blockade globally or in peripheral tissues only is also discussed.
This review surveys the role of endocannabinoids in alcohol drinking behavior as well as alcohol‐induced organ damage. Highlighted are recent findings that peripheral endocannabinoids acting in the stomach promote alcohol drinking by modulating ghrelin signaling via a gut/brain axis. Another highlight is evidence for a bidirectional metabolic synapse in the liver whereby alcohol‐exposed hepatocytes release glutamate that stimulates metabotropic glutamate receptors on stellate cells to induce the synthesis of 2‐arachidonoylglycerol, which acts on hepatocyte CB1‐receptors to promote lipogenesis.
The emergence of novel psychoactive substances (NPS), particularly synthetic cannabinoid receptor agonists (SCRA), has involved hundreds of potentially harmful chemicals in a highly dynamic ...international market challenging users', clinicians', and regulators' understanding of what circulating substances are causing harm. We describe a toxicovigilance system for NPS that predicted the UK emergence and identified the clinical toxicity caused by novel indole and indazole carboxylate SCRA.
To assist early accurate identification, we synthesized 5 examples of commercially unavailable indole and indazole carboxylate SCRA (FUB-NPB-22, 5F-NPB-22, 5F-SDB-005, FUB-PB-22, NM-2201). We analyzed plasma and urine samples from 160 patients presenting to emergency departments with severe toxicity after suspected NPS use during 2015 to 2016 for these and other NPS using data-independent LC-MS/MS.
We successfully synthesized 5 carboxylate SCRAs using established synthetic and analytical chemistry methodologies. We identified at least 1 SCRA in samples from 49 patients, including an indole or indazole carboxylate SCRA in 17 (35%), specifically 5F-PB-22 (14%), FUB PB-22 (6%), BB-22 (2%), 5F NPB-22 (20%), FUB NPB-22 (2%), and 5F-SDB-005 (4%). In these 17 patients, there was analytical evidence of other substances in 16. Clinical features included agitation and aggression (82%), reduced consciousness (76%), acidosis (47%), hallucinations and paranoid features (41%), tachycardia (35%), hypertension (29%), raised creatine kinase (24%), and seizures (12%).
This toxicovigilance system predicted the emergence of misuse of indole and indazole carboxylate SCRA, documented associated clinical harms, and notified relevant agencies. Toxicity appears consistent with other SCRA, including mental state disturbances and reduced consciousness.
Abstract
Der Cannabinoid 2 Rezeptor (CB
2
R) besitzt großes therapeutisches Potential bei zahlreichen pathophysiologischen Prozessen wie z. B. der Neuroinflammation. Signalweg‐selektive Liganden ...werden benötigt, um mangelnden klinischen Erfolg zu überwinden und um die Zusammenhänge zwischen einzelnen Signalwegen und deren therapeutischen Effekten zu beleuchten. Hier berichten wir vom Design und der Synthese eines photoschaltbaren chemischen Gerüsts basierend auf der “privilegierten” Struktur des Benzimidazols und seiner Anwendung als funktionell selektiven CB
2
R “Wirksamkeitsschalter” (”efficacy switch”). Benzimidazol‐Azo‐Arene bieten großes Potential für eine breite Erweiterung der Photopharmakologie auf eine Vielzahl optisch adressierbarer biologischer Zielstrukturen. Wir haben dieses Gerüst verwendet, um Substanz
10 d
zu entwickeln, ein “
trans
‐on” Agonist, der als molekulare Sonde dient, um den β‐Arrestin2 (βArr2) Signalweg am CB
2
R zu untersuchen. Die selektive Aktivierung des βΑrr2 Signalweges wurde mittels CB
2
R Internalisierung und βArr2 Rekrutierung nachgewiesen, während keine Aktivierung bei der Betrachtung von Gα
16
oder mini‐Gα
i
auftrat. Insgesamt stellt Substanz
10 d
den ersten Licht‐abhängigen funktionell selektiven Agonisten dar, mit dem die komplexen βArr2‐abhängigen Mechanismen der Endozytose am CB
2
R untersucht werden können.
Astrocytes take up glucose from the bloodstream to provide energy to the brain, thereby allowing neuronal activity and behavioural responses
. By contrast, astrocytes are under neuronal control ...through specific neurotransmitter receptors
. However, whether the activation of astroglial receptors can directly regulate cellular glucose metabolism to eventually modulate behavioural responses is unclear. Here we show that activation of mouse astroglial type-1 cannabinoid receptors associated with mitochondrial membranes (mtCB
) hampers the metabolism of glucose and the production of lactate in the brain, resulting in altered neuronal functions and, in turn, impaired behavioural responses in social interaction assays. Specifically, activation of astroglial mtCB
receptors reduces the phosphorylation of the mitochondrial complex I subunit NDUFS4, which decreases the stability and activity of complex I. This leads to a reduction in the generation of reactive oxygen species by astrocytes and affects the glycolytic production of lactate through the hypoxia-inducible factor 1 pathway, eventually resulting in neuronal redox stress and impairment of behavioural responses in social interaction assays. Genetic and pharmacological correction of each of these effects abolishes the effect of cannabinoid treatment on the observed behaviour. These findings suggest that mtCB
receptor signalling can directly regulate astroglial glucose metabolism to fine-tune neuronal activity and behaviour in mice.
The aim of the research was to assess the impact of O-1602-novel GPR55 and GPR18 agonist-in the rat model of detrusor overactivity (DO). Additionally, its effect on the level of specific biomarkers ...was examined. To stimulate DO, 0.75% retinyl acetate (RA) was administered to female rats' bladders. O-1602, at a single dose of 0.25 mg/kg, was injected intra-arterially during conscious cystometry. Furthermore, heart rate, blood pressure, and urine production were monitored for 24 h, and the impact of O-1602 on the levels of specific biomarkers was evaluated. An exposure of the urothelium to RA changed cystometric parameters and enhanced the biomarker levels. O-1602 did not affect any of the examined cystometric parameters or levels of biomarkers in control rats. However, the O-1602 injection into animals with RA-induced DO ameliorated the symptoms of DO and caused a reversal in the described changes in the concentration of CGRP, OCT
, BDNF, and NGF to the levels observed in the control, while the values of ERK1/2 and VAChT were significantly lowered compared with the RA-induced DO group, but were still statistically higher than in the control. O-1602 can improve DO, and may serve as a promising novel substance for the pharmacotherapy of bladder diseases.
The endocannabinoid system has been found to be pervasive in mammalian species. It has also been described in invertebrate species as primitive as the Hydra. Insects, apparently, are devoid of this, ...otherwise, ubiquitous system that provides homeostatic balance to the nervous and immune systems, as well as many other organ systems. The endocannabinoid system (ECS) has been defined to consist of three parts, which include (1) endogenous ligands, (2) G-protein coupled receptors (GPCRs), and (3) enzymes to degrade and recycle the ligands. Two endogenous molecules have been identified as ligands in the ECS to date. The endocannabinoids are anandamide (arachidonoyl ethanolamide) and 2-AG (2-arachidonoyl glycerol). Two G-coupled protein receptors (GPCR) have been described as part of this system, with other putative GPC being considered. Coincidentally, the phytochemicals produced in large quantities by the Cannabis sativa L plant, and in lesser amounts by other plants, can interact with this system as ligands. These plant-based cannabinoids are termed phytocannabinoids. The precise determination of the distribution of cannabinoid receptors in animal species is an ongoing project, with the canine cannabinoid receptor distribution currently receiving the most interest in non-human animals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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