scholarly journals Cyclooxygenase-2 inhibition reduces stress-induced affective pathology

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Joyonna Carrie Gamble-George ◽  
Rita Baldi ◽  
Lindsay Halladay ◽  
Adrina Kocharian ◽  
Nolan Hartley ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Basolateral Amygdala ◽  
Cannabinoid Receptor ◽  
Ex Vivo ◽  
Receptor Activation ◽  
Cyclooxygenase 2 ◽  
Novel Treatment ◽  
Cox 2 ◽  
Cox 2 Inhibitors

Mood and anxiety disorders are the most prevalent psychiatric conditions and are exacerbated by stress. Recent studies have suggested cyclooxygenase-2 (COX-2) inhibition could represent a novel treatment approach or augmentation strategy for affective disorders including anxiety disorders and major depression. We show that traditional COX-2 inhibitors and a newly developed substrate-selective COX-2 inhibitor (SSCI) reduce a variety of stress-induced behavioral pathologies in mice. We found that these behavioral effects were associated with a dampening of neuronal excitability in the basolateral amygdala (BLA) ex vivo and in vivo, and were mediated by small-conductance calcium-activated potassium (SK) channel and CB1 cannabinoid receptor activation. Taken together, these data provide further support for the potential utility of SSCIs, as well as traditional COX-2 inhibitors, as novel treatment approaches for stress-related psychiatric disorders.

scholarly journals 2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2850 ◽  
Author(s):  
Michelle Cortes-Salva ◽  
Stal Shrestha ◽  
Prachi Singh ◽  
Cheryl Morse ◽  
Kimberly Jenko ◽  
...  
Keyword(s):  
Comparative Evaluation ◽  
Cyclooxygenase 2 ◽  
Emission Tomography ◽  
Inhibitory Potency ◽  
Positron Emission ◽  
Positron Emitter ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Cyclooxygenase 2 (COX-2) is an inducible enzyme responsible for the conversion of arachidonic acid into the prostaglandins, PGG2 and PGH2. Expression of this enzyme increases in inflammation. Therefore, the development of probes for imaging COX-2 with positron emission tomography (PET) has gained interest because they could be useful for the study of inflammation in vivo, and for aiding anti-inflammatory drug development targeting COX-2. Nonetheless, effective PET radioligands are still lacking. We synthesized eleven COX-2 inhibitors based on a 2(4-methylsulfonylphenyl)pyrimidine core from which we selected three as prospective PET radioligands based on desirable factors, such as high inhibitory potency for COX-2, very low inhibitory potency for COX-1, moderate lipophilicity, and amenability to labeling with a positron-emitter. These inhibitors, namely 6-methoxy-2-(4-(methylsulfonyl)phenyl-N-(thiophen-2ylmethyl)pyrimidin-4-amine (17), the 6-fluoromethyl analogue (20), and the 6-(2-fluoroethoxy) analogue (27), were labeled in useful yields and with high molar activities by treating the 6-hydroxy analogue (26) with [11C]iodomethane, [18F]2-fluorobromoethane, and [d2-18F]fluorobromomethane, respectively. [11C]17, [18F]20, and [d2-18F]27 were readily purified with HPLC and formulated for intravenous injection. These methods allow these radioligands to be produced for comparative evaluation as PET radioligands for measuring COX-2 in healthy rhesus monkey and for assessing their abilities to detect inflammation.

scholarly journals In Silico Molecular Docking Studies of Lichen Metabolites against Cyclooxygenase-2 Enzyme

2015 ◽  
Vol 18 (2) ◽  
pp. 90-96 ◽  
Author(s):  
Mohammad Firoz Khan ◽  
Sabreena Aleem Nabila ◽  
Ridwan Bin Rashid ◽  
Mohammad Sharifur Rahman ◽  
Abu Asad Chowdhury ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Usnic Acid ◽  
Cyclooxygenase 2 ◽  
Therapeutic Effects ◽  
Lichen Metabolites ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 2 Inhibitors

Cyclooxygenase-2 (COX-2) is an inducible enzyme that causes inflammation. COX-2 inhibitors are clinically effective anti-inflammatory agents with less gastrointestinal and renal toxicities. However, they lack anti-thrombotic activity and hence lead to increased incidences of adverse cardiovascular thrombotic events, including myocardial infarction. Therefore, there is still need to develop COX-2 inhibitors with better therapeutic effects and tolerability. The aim of the present study is to explore the anti-inflammatory activity of five lichen metabolites by conducting virtual screenings. In this regard, molecular docking simulations were carried out for the lichen metabolites namely atranorin, diffractic acid, lecanoric acid, salazinic acid and usnic acid with human COX-2 enzyme and the docked results were compared with the standard reference ligands (Celecoxib and Rofecoxib). Among all the docked ligands, the lecanoric acid demonstrated best binding affinity -9.83 kcal/mol followed by atranorin (-8.7 kcal/mol) and diffractic acid (-8.6 kcal/mol) which are comparable to the reference ligands celecoxib (-12.3 kcal/mol) and rofecoxib (-11.2 kcal/mol). The salazinic acid and usnic acid has shown binding affinity of -7.9 kcal/mol and -4.7 kcal/mol, respectively. Moreover, all the ligands except atranorin and diffractic acid satisfied Lipinski’s rule of 5. From the docking results it was revealed that the lichen metabolites might have inhibitory activity against COX-2 enzyme, and are expected to be useful in conducting in vivo anti-inflammatory screenings on animal model which may lead to the development of more effective and potent new chemical entities with anti-inflammatory properties.Bangladesh Pharmaceutical Journal 18(2): 90-96, 2015

Reflectance Spectroscopy of Clotting Blood: A Description of the Time-Dependent Behavior

2004 ◽  
Vol 128 (2) ◽  
pp. 173-180
Author(s):  
Frank A. Greco
Keyword(s):  
Light Intensity ◽  
Whole Blood ◽  
Time Course ◽  
Ex Vivo ◽  
Reflectance Spectroscopy ◽  
Cyclooxygenase 2 ◽  
Terminal Phase ◽  
Reflected Light ◽  
Cox 2 ◽  
Cox 2 Inhibitors

Abstract Context.—Research into whether cyclooxygenase-2 (COX-2) inhibitors affect thrombosis has been hampered by the lack of a specific assay. Erythrocytes modulate the effect of aspirin on platelets, which suggests that tests of whole blood clotting may be more sensitive. Objectives.—To determine whether reflectance spectroscopy of clotting blood generates useful information about coagulation and whether it shows an effect of COX-2 inhibitors. Design.—A survey of 14 adults examined the range of phenomena demonstrated by reflectance spectroscopy. These phenomena were compared before and after treatment with a COX-2 inhibitor in 4 subjects. Setting.—Out-patient clinic. Main Outcome Measure.—Reflected light intensity was measured from blood as it clotted in a cuvette thermostated at 37°C. Results.—The survey of healthy adults showed that the time course of reflected light intensity is similar at all wavelengths and may be divided into 4 stages: a monotonic decrease, a sigmoidal increase, a linear region, and a terminal phase. Clot formation as determined by tube inversion occurs at the transition between the first and second phases; the sigmoidal increase cannot be due to fibrin polymerization. The terminal phase coincides with clot retraction. Similar results are obtained in native whole blood and in recalcified citrated blood. Cyclooxygenase-2 inhibitors have an intrinsic effect on the sigmoidal increase ex vivo (P < .001). Conclusions.—Reflectance spectroscopy generates unique information about clotting blood. It is feasible to use anticoagulated blood to elucidate the events underlying the time course and to investigate the effects of COX-2 inhibitors.

scholarly journals In Silico, In Vitro, and In Vivo Analysis of Tanshinone IIA and Cryptotanshinone from Salvia miltiorrhiza as Modulators of Cyclooxygenase-2/mPGES-1/Endothelial Prostaglandin EP3 Pathway

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 99
Author(s):  
Anella Saviano ◽  
Simona De Vita ◽  
Maria Giovanna Chini ◽  
Noemi Marigliano ◽  
Gianluigi Lauro ◽  
...  
Keyword(s):  
In Silico ◽  
Ex Vivo ◽  
Salvia Miltiorrhiza ◽  
Cyclooxygenase 2 ◽  
Tanshinone Iia ◽  
Prostaglandin E ◽  
Platelet Activity ◽  
Cox 2

Tanshinone IIA (TIIA) and cryptotanshinone (CRY) from Salvia miltiorrhiza Bunge were investigated for their inhibitory activity against the cyclooxygenase-2 (COX-2)/microsomal prostaglandin E synthase-1 (mPGES-1)/endothelial prostaglandin 3 (EP3) pathway using in silico, in vitro, in vivo, and ex vivo assays. From the analysis of the docking poses, both diterpenoids were able to interact significantly with COX-2, 5-lipoxygenase (5-LO), platelet-activating factor receptor (PAFR), and mPGES-1. This evidence was further corroborated by data obtained from a cell-free assay, where CRY displayed a significant inhibitory potency against mPGES-1 (IC50 = 1.9 ± 0.4 µM) and 5-LO (IC50 = 7.1 µM), while TIIA showed no relevant inhibition of these targets. This was consistent with their activity to increase mice bleeding time (CRY: 2.44 ± 0.13 min, p ≤ 0.001; TIIA: 2.07 ± 0.17 min p ≤ 0.01) and with the capability to modulate mouse clot retraction (CRY: 0.048 ± 0.011 g, p ≤ 0.01; TIIA: 0.068 ± 0.009 g, p ≤ 0.05). For the first time, our results show that TIIA and, in particular, CRY are able to interact significantly with the key proteins involved not only in the onset of inflammation but also in platelet activity (and hyper-reactivity). Future preclinical and clinical investigations, together with this evidence, could provide the scientific basis to consider these compounds as an alternative therapeutic approach for thrombotic- and thromboembolic-based diseases.

scholarly journals Radiosynthesis and Preclinical Evaluation of 11C-VA426, a Cyclooxygenase-2 Selective Ligand

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Assunta Carpinelli ◽  
Paolo Rainone ◽  
Sara Belloli ◽  
Annalisa Reale ◽  
Andrea Cappelli ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Radiochemical Yield ◽  
Cyclooxygenase 2 ◽  
Peripheral Tissues ◽  
Biodistribution Studies ◽  
Selective Ligand ◽  
Cox 2 ◽  
Rats And Mice ◽  
Ex Vivo Biodistribution

Cyclooxygenase-2 (COX-2) is involved in the inflammatory response, and its recurrent overexpression in cancers as well as in neurodegenerative disorders has made it an important target for therapy. For this reason, noninvasive imaging of COX-2 expression may represent an important diagnostic tool. In this work, a COX-2 inhibitor analogue, VA426 [1-(4-fluorophenyl)-3-(2-methoxyethyl)-2-methyl-5-(4-(methylsulfonil)phenyl)-1H-pyrrole], was synthesized and radiolabelled with the 11C radioisotope. The ex vivo biodistribution profile of 11C-VA426 was evaluated in the brain and periphery of healthy rats and mice and in brain and periphery of inflammation models, based on the administration of LPS. 11C-VA426 synthesis with the tBuOK base showed optimal radiochemical yield (15 ± 2%) based on triflate activity, molar activity (range 37–148 GBq/μmol), and radiochemical purity (>95%). Ex vivo biodistribution studies showed a fast uptake of radioactivity but a rapid washout, except in regions expressing COX-2 (lungs, liver, and kidney) both in rats and in mice, with maximum values at 30 and 10 minutes p.i., respectively. LPS administration did not show significant effect on radioactivity accumulation. Celecoxib competition experiments performed in rats and mice treated with LPS produced a general target unrelated reduction of radioactivity concentration in all peripheral tissues and brain areas examined. Finally, in agreement with the negative results obtained from biodistribution experiments, radiometabolites analysis revealed that 11C-VA426 is highly unstable in vivo. This study indicates that the compound 11C-VA426 is not currently suitable to be used as radiopharmaceutical for PET imaging. This family of compounds needs further implementation in order to improve in vivo stability.

scholarly journals β-Caryophyllene inhibits monoacylglycerol lipase activity and increases 2-AG levels: a new mechanism of endocannabinoid-mediated analgesia?

2021 ◽  
Author(s):  
Jost Klawitter ◽  
Weibke Weissenborn ◽  
MacKenzie Walz ◽  
Jelena Klawitter ◽  
Matthew Jackson ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Ex Vivo ◽  
Receptor Activation ◽  
Monoacylglycerol Lipase ◽  
Tissue Samples ◽  
Pain Model ◽  
Surgical Pain ◽  
Dose Dependent

Introduction. β-Caryophyllene (BCP) has been shown to be an effective anti-inflammatory agent in chronic and inflammatory pain models. Since limited data are available for BCP in acute pain, we tested efficacy of BCP in an acute post-surgical pain model. Methods. BCP was tested in an acute postsurgical pain model. Animals were treated with vehicle, 10, 25, 50 and 75 mg/kg BCP that was injected intra-peritoneally (i.p.). Time dependent paw withdrawal response (PWR) were evaluated using von Frey filaments and plasma and tissue samples were taken. BCP levels were determined in tissue (paw and spine) and plasma using an HPLC-MS based approach. Endocannabinoids (2-arachidonoylglycerol) were also evaluated in plasma and tissues using an HPLC-MS based approach. Monoacylglycerol lipase (MAGL) activity was evaluated in-vitro as well as ex vivo. Results. A dose-dependent improvement of hyperalgesia was observed up to 85% of the baseline value 30 minutes after administration of the highest BCP dose of 75 mg/kg. A BCP dose-dependent increase in the 2-arachidonoylglycerol (2-AG) levels was observed with 9.9 ± 6.4 ng/mL in the 75 mg/kg dose group as compared to vehicle controls with 3.0 ± 2.5 ng/mL. In vitro MAGL enzyme activity assessment using 2-AG as the substrate revealed an IC50 of 7.4 µM of BCP for MAGL inhibition. Conclusion. These data showed that BCP inhibits MAGL activity in-vitro and in-vivo causing 2-AG levels to rise. Since the endocannabinoid 2-AG is a CB1 and CB2 receptor agonist, we propose the 2-AG-mediated cannabinoid receptor activation may contribute to BCP’s mechanism of analgesia.

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