scholarly journals Experimental Cannabinoid 2 Receptor Activation by Phyto-Derived and Synthetic Cannabinoid Ligands in LPS-Induced Interstitial Cystitis in Mice

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4239 ◽  
Author(s):  
Geraint Berger ◽  
Nipun Arora ◽  
Ian Burkovskiy ◽  
Yanfang Xia ◽  
Anu Chinnadurai ◽  
...  
Keyword(s):  
Interstitial Cystitis ◽  
Cannabinoid Receptors ◽  
Oral Treatment ◽  
Endocannabinoid System ◽  
Receptor Activation ◽  
Synthetic Cannabinoid ◽  
Capillary Perfusion ◽  
Bladder Inflammation ◽  
Alternative Treatment Option ◽  
Anti Inflammatory

Interstitial cystitis (IC) is a chronic bladder disorder with unclear etiology. The endocannabinoid system has been identified as a key regulator of immune function, with experimental evidence for the involvement of cannabinoid receptors in bladder inflammation. This study used intravital microscopy (IVM) and behavioral testing in lipopolysaccharide-induced IC, to investigate the anti-inflammatory analgesic effects of a natural dietary sesquiterpenoid, beta-caryophyllene (BCP), which is present in cannabis among other plants, and has reported agonist actions at the cannabinoid 2 receptor (CB2R). BCP’s anti-inflammatory actions were compared to the synthetic CB2R-selective cannabinoid, HU308, and to an FDA-approved clinical treatment (dimethyl sulfoxide: DMSO). IVM data revealed that intravesical instillation of BCP and/or HU308 significantly reduces the number of adhering leukocytes in submucosal bladder venules and improves bladder capillary perfusion. The effects of BCP were found to be comparable to that of the selective CB2R synthetic cannabinoid, HU308, and superior to intravesical DMSO treatment. Oral treatment with BCP was also able to reduce bladder inflammation and significantly reduced mechanical allodynia in experimental IC. Based on our findings, we believe that CB2R activation may represent a viable therapeutic target for IC, and that drugs that activate CB2R, such as the generally regarded as safe (GRAS) dietary sesquiterpenoid, BCP, may serve as an adjunct and/or alternative treatment option for alleviating symptoms of inflammation and pain in the management of IC.

scholarly journals Activity-Based Detection of Cannabinoids in Serum and Plasma Samples

2018 ◽  
Vol 64 (6) ◽  
pp. 918-926 ◽  
Author(s):  
Annelies Cannaert ◽  
Jolien Storme ◽  
Cornelius Hess ◽  
Volker Auwärter ◽  
Sarah M R Wille ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoids ◽  
Receptor Activation ◽  
Synthetic Cannabinoid ◽  
New Psychoactive Substances ◽  
Simple Liquid ◽  
Analytical Sensitivity ◽  
Monitoring Centre ◽  
Screening Strategies

Abstract BACKGROUND Synthetic cannabinoids are the largest group of new psychoactive substances monitored by the European Monitoring Centre of Drugs and Drug Addiction. The rapid proliferation of novel analogs makes the detection of these new derivatives challenging and has initiated considerable interest in the development of so-called “untargeted” screening strategies to detect these compounds. METHODS We developed new, stable bioassays in which cannabinoid receptor activation by cannabinoids led to recruitment of truncated β-arrestin 2 (βarr2) to the cannabinoid receptors, resulting in functional complementation of a split luciferase, allowing readout via bioluminescence. Aliquots (500 μL) of authentic serum (n = 45) and plasma (n = 73) samples were used for simple liquid–liquid extraction with hexane:ethyl acetate (99:1 v/v). Following evaporation and reconstitution in 100 μL of Opti-MEM® I/methanol (50/50 v/v), 10 μL of these extracts was analyzed in the bioassays. RESULTS Truncation of βarr2 significantly (for both cannabinoid receptors; P = 0.0034 and 0.0427) improved the analytical sensitivity over the previously published bioassays applied on urine samples. The new bioassays detected cannabinoid receptor activation by authentic serum or plasma extracts, in which synthetic cannabinoids were present at low- or sub-nanogram per milliliter concentration or in which Δ9-tetrahydrocannabinol was present at concentrations >12 ng/mL. For synthetic cannabinoid detection, analytical sensitivity was 82%, with an analytical specificity of 100%. CONCLUSIONS The bioassays have the potential to serve as a first-line screening tool for (synthetic) cannabinoid activity in serum or plasma and may complement conventional analytical assays and/or precede analytical (mass spectrometry based) confirmation.

scholarly journals Update on the Role of Cannabinoid Receptors after Ischemic Stroke

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Luciano S. A. Capettini ◽  
Silvia Q. Savergnini ◽  
Rafaela F. da Silva ◽  
Nikos Stergiopulos ◽  
Robson A. S. Santos ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cannabinoid Receptors ◽  
Inflammatory Diseases ◽  
Receptor Activation ◽  
Protective Effects ◽  
Peripheral Tissues ◽  
Transmembrane Receptors ◽  
Anti Inflammatory

Cannabinoids are considered as key mediators in the pathophysiology of inflammatory diseases, including atherosclerosis. In particular, they have been shown to reduce the ischemic injury after acute cardiovascular events, such as acute myocardial infarction and ischemic stroke. These protective and anti-inflammatory properties on peripheral tissues and circulating inflammatory have been demonstrated to involve their binding with both selective cannabinoid type 1 (CB1) and type 2 (CB2) transmembrane receptors. On the other hands, the recent discoveries of novel different classes of cannabinoids and receptors have increased the complexity of this system in atherosclerosis. Although only preliminary data have been reported on the activities of novel cannabinoid receptors, several studies have already investigated the role ofCB1andCB2receptors in ischemic stroke. WhileCB1receptor activation has been shown to directly reduce atherosclerotic plaque inflammation, controversial data have been shown on neurotransmission and neuroprotection after stroke. Given its potent anti-inflammatory activities on circulating leukocytes, theCB2activation has been proven to produce protective effects against acute poststroke inflammation. In this paper, we will update evidence on different cannabinoid-triggered avenues to reduce inflammation and neuronal injury in acute ischemic stroke.

Oral treatment with a vitamin D3 analogue (BXL628) has anti-inflammatory effects in rodent model of interstitial cystitis

2006 ◽  
Vol 97 (3) ◽  
pp. 617-624 ◽  
Author(s):  
FABIO BENIGNI ◽  
ENRICO BARONI ◽  
MARIJA ZECEVIC ◽  
PETER ZVARA ◽  
TOMI STRENG ◽  
...  
Keyword(s):  
Interstitial Cystitis ◽  
Vitamin D3 ◽  
Oral Treatment ◽  
Rodent Model ◽  
Anti Inflammatory

Endocannabinoids and Food Intake: Newborn Suckling and Appetite Regulation in Adulthood

2005 ◽  
Vol 230 (4) ◽  
pp. 225-234 ◽  
Author(s):  
Ester Fride ◽  
Tatyana Bregman ◽  
Tim C. Kirkham
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Critical Role ◽  
Growth Failure ◽  
Endocannabinoid System ◽  
Failure To Thrive ◽  
Receptor Activation ◽  
Organ Systems

The appetite-stimulating effects of the cannabis plant (Cannabis sativa) have been known since ancient times, and appear to be effected through the incentive and rewarding properties of foods. Investigations into the biological basis of the multiple effects of cannabis have yielded important breakthroughs in recent years: the discovery of two cannabinoid receptors in brain and peripheral organ systems, and endogenous ligands (endocannabinoids) for these receptors. These advances have greatly increased our understanding of how appetite is regulated through these endocannabinoid receptor systems. The presence of endocannabinoids in the developing brain and in maternal milk have led to evidence for a critical role for CB, receptors in oral motor control of suckling during neonatal development. The endocannabinoids appear to regulate energy balance and food intake at four functional levels within the brain and periphery: (i) limbic system (for hedonic evaluation of foods), (ii) hypothalamus and hindbrain (integrative functions), (iii) intestinal system, and (iv) adipose tissue. At each of these levels, the endocannabinoid system interacts with a number of better known molecules involved in appetite and weight regulation, including leptin, ghrelin, and the melanocortins. Therapeutically, appetite stimulation by cannabinoids has been studied for several decades, particularly in relation to cachexia and malnutrition associated with cancer, acquired immunodeficiency syndrome, or anorexia nervosa. The recent advances in cannabinoid pharmacology may lead to improved treatments for these conditions or, conversely, for combating excessive appetite and body weight, such as CB, receptor antagonists as antiobesity medications. In conclusion, the exciting progress in the understanding of how the endocannabinoid CB receptor systems influence appetite and body weight is stimulating the development of therapeutic orexigenic and anorectic agents. Furthermore, the role of cannabinoid CB, receptor activation for milk suckling in newborns may open new doors toward understanding nonorganic failure-to-thrive in infants, who display growth failure without known organic cause.

Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms

2013 ◽  
Vol 304 (2) ◽  
pp. G181-G192 ◽  
Author(s):  
Thomas Michler ◽  
Martin Storr ◽  
Johannes Kramer ◽  
Stefanie Ochs ◽  
Antje Malo ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Western Blotting ◽  
Map Kinases ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Receptor Activation ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Pancreatic Acini

The endocannabinoid system has been shown to mediate beneficial effects on gastrointestinal inflammation via cannabinoid receptors 1 (CB1) and 2 (CB2). These receptors have also been reported to activate the MAP kinases p38 and c-Jun NH2-terminal kinase (JNK), which are involved in early acinar events leading to acute pancreatitis and induction of proinflammatory cytokines. Our aim was to examine the role of cannabinoid receptor activation in an experimental model of acute pancreatitis and the potential involvement of MAP kinases. Cerulein pancreatitis was induced in wild-type, CB1−/−, and MK2−/− mice pretreated with selective cannabinoid receptor agonists or antagonists. Severity of pancreatitis was determined by serum amylase and IL-6 levels, intracellular activation of pancreatic trypsinogen, lung myeloperoxidase activity, pancreatic edema, and histological examinations. Pancreatic lysates were investigated by Western blotting using phospho-specific antibodies against p38 and JNK. Quantitative PCR data, Western blotting experiments, and immunohistochemistry clearly show that CB1 and CB2 are expressed in mouse pancreatic acini. During acute pancreatitis, an upregulation especially of CB2 on apoptotic cells occurred. The unselective CB1/CB2 agonist HU210 ameliorated pancreatitis in wild-type and CB1−/− mice, indicating that this effect is mediated by CB2. Furthermore, blockade of CB2, not CB1, with selective antagonists engraved pathology. Stimulation with a selective CB2 agonist attenuated acute pancreatitis and an increased activation of p38 was observed in the acini. With use of MK2−/− mice, it could be demonstrated that this attenuation is dependent on MK2. Hence, using the MK2−/− mouse model we reveal a novel CB2-activated and MAP kinase-dependent pathway that modulates cytokine expression and reduces pancreatic injury and affiliated complications.

scholarly journals Characterization of Endocannabinoid System and Interleukin Profiles in Ovine AEC: Cannabinoid Receptors Type-1 and Type-2 as Key Effectors of Pro-Inflammatory Response

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1008 ◽  
Author(s):  
Luana Greco ◽  
Valentina Russo ◽  
Cinzia Rapino ◽  
Clara Di Germanio ◽  
Filomena Fezza ◽  
...  
Keyword(s):  
Immune Modulation ◽  
Cannabinoid Receptors ◽  
Endocannabinoid System ◽  
Middle Stage ◽  
Selective Agonists ◽  
Anti Inflammatory

Amniotic epithelial cells (AEC) have been proposed as promising clinical candidates for regenerative medicine therapies due to their immunomodulatory capacity. In this context, the endocannabinoid system (ECS) has been identified as mediating the immune-stem cell dialogue, even if no information on AEC is available to date. Therefore, this study was designed to assess whether ECS is involved in tuning the constitutive and lipopolysaccharide (LPS)-induced ovine AEC anti-inflammatory and pro-inflammatory interleukin (IL-10, IL-4, and IL-12) profiles. Firstly, interleukins and ECS expressions were studied at different stages of gestation. Then, the role of cannabinoid receptors 1 and 2 (CB1 and CB2) on interleukin expression and release was investigated in middle stage AEC using selective agonists and antagonists. AEC displayed a degradative more than a synthetic endocannabinoid metabolism during the early and middle stages of gestation. At the middle stage, cannabinoid receptors mediated the balance between pro-inflammatory (IL-12) and anti-inflammatory (IL-4 and IL-10) interleukins. The activation of both receptors mediated an overall pro-inflammatory shift—CB1 reduced the anti-inflammatory and CB2 increased the pro-inflammatory interleukin release, particularly after LPS stimulation. Altogether, these data pave the way for the comprehension of AEC mechanisms tuning immune-modulation, crucial for the development of new AEC-based therapy protocols.

scholarly journals Cannabidiol as a Therapeutic Target: Evidence of its Neuroprotective and Neuromodulatory Function in Parkinson’s Disease

2020 ◽  
Vol 11 ◽  
Author(s):  
Felipe Patricio ◽  
Alan Axel Morales-Andrade ◽  
Aleidy Patricio-Martínez ◽  
Ilhuicamina Daniel Limón
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Therapeutic Potential ◽  
Endocannabinoid System ◽  
Receptor Activation ◽  
Subcortical Structures ◽  
6 Hydroxydopamine

The phytocannabinoids of Cannabis sativa L. have, since ancient times, been proposed as a pharmacological alternative for treating various central nervous system (CNS) disorders. Interestingly, cannabinoid receptors (CBRs) are highly expressed in the basal ganglia (BG) circuit of both animals and humans. The BG are subcortical structures that regulate the initiation, execution, and orientation of movement. CBRs regulate dopaminergic transmission in the nigro-striatal pathway and, thus, the BG circuit also. The functioning of the BG is affected in pathologies related to movement disorders, especially those occurring in Parkinson’s disease (PD), which produces motor and non-motor symptoms that involving GABAergic, glutamatergic, and dopaminergic neural networks. To date, the most effective medication for PD is levodopa (l-DOPA); however, long-term levodopa treatment causes a type of long-term dyskinesias, l-DOPA-induced dyskinesias (LIDs). With neuromodulation offering a novel treatment strategy for PD patients, research has focused on the endocannabinoid system (ECS), as it participates in the physiological neuromodulation of the BG in order to control movement. CBRs have been shown to inhibit neurotransmitter release, while endocannabinoids (eCBs) play a key role in the synaptic regulation of the BG. In the past decade, cannabidiol (CBD), a non-psychotropic phytocannabinoid, has been shown to have compensatory effects both on the ECS and as a neuromodulator and neuroprotector in models such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and reserpine, as well as other PD models. Although the CBD-induced neuroprotection observed in animal models of PD has been attributed to the activation of the CB1 receptor, recent research conducted at a molecular level has proposed that CBD is capable of activating other receptors, such as CB2 and the TRPV-1 receptor, both of which are expressed in the dopaminergic neurons of the nigro-striatal pathway. These findings open new lines of scientific inquiry into the effects of CBD at the level of neural communication. Cannabidiol activates the PPARγ, GPR55, GPR3, GPR6, GPR12, and GPR18 receptors, causing a variety of biochemical, molecular, and behavioral effects due to the broad range of receptors it activates in the CNS. Given the low number of pharmacological treatment alternatives for PD currently available, the search for molecules with the therapeutic potential to improve neuronal communication is crucial. Therefore, the investigation of CBD and the mechanisms involved in its function is required in order to ascertain whether receptor activation could be a treatment alternative for both PD and LID.

scholarly journals Endocannabinoid System and Ocular Vascularization

2018 ◽  
Vol 10 (2) ◽  
pp. 168-175 ◽  
Author(s):  
Raluca Iancu ◽  
Ioana-Cristina Coman ◽  
Cosmina Barac ◽  
Mohammad Al Hammoud ◽  
Alina Popa Cherecheanu
Keyword(s):  
Intraocular Pressure ◽  
Clinical Research ◽  
Cannabinoid Receptors ◽  
Endocannabinoid System ◽  
Systemic Circulation ◽  
System Complexity ◽  
Ocular Circulation ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

The focus of this review is the role of endocannabinoid system in ocular and systemic circulation. By critically examining preclinical and clinical research, we explore the cannabinoid receptors localization and vascular implications as well as their interaction with other anti-inflammatory drugs. The objective is to transfer knowledge on the use of cannabinoids, specifically their effect on ocular circulation and intraocular pressure, and provide a better understanding of the endocannabinoid system complexity in modulating local and systemic circulations in order to identify potential uses and limitations of cannabinoid-based therapeutics.  

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