Background and Purpose
Cannabidiol has been reported to act as an antagonist at cannabinoid CB1 receptors. We hypothesized that cannabidiol would inhibit cannabinoid agonist activity through negative ...allosteric modulation of CB1 receptors.
Experimental Approach
Internalization of CB1 receptors, arrestin2 recruitment, and PLCβ3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB1 receptors and in the STHdhQ7/Q7 cell model of striatal neurons endogenously expressing CB1 receptors. Cells were treated with 2‐arachidonylglycerol or Δ9‐tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol.
Key Results
Cannabidiol reduced the efficacy and potency of 2‐arachidonylglycerol and Δ9‐tetrahydrocannabinol on PLCβ3‐ and ERK1/2‐dependent signalling in cells heterologously (HEK 293A) or endogenously (STHdhQ7/Q7) expressing CB1 receptors. By reducing arrestin2 recruitment to CB1 receptors, cannabidiol treatment prevented internalization of these receptors. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino terminus of the CB1 receptor.
Conclusions and Implications
Cannabidiol behaved as a non‐competitive negative allosteric modulator of CB1 receptors. Allosteric modulation, in conjunction with effects not mediated by CB1 receptors, may explain the in vivo effects of cannabidiol. Allosteric modulators of CB1 receptors have the potential to treat CNS and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of these receptors.
The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited ...statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever ...worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.
Background and Purpose
Cannabinoid CB2 receptors mediate immunomodulation. Here, we investigated the effects of CB2 receptor ligands on leukocyte‐endothelial adhesion and inflammatory mediator ...release in experimental endotoxin‐induced uveitis (EIU).
Experimental Approach
EIU was induced by intraocular injection of lipopolysaccharide (LPS, 20 ng·μL−1). Effects of the CB2 receptor agonist, HU308 (1.5% topical), the CB2 receptor antagonist, AM630 (2.5 mg·kg−1 i.v.), or a combination of both compounds on leukocyte‐endothelial interactions were measured hourly for 6 h in rat iridial vasculature using intravital microscopy. Anti‐inflammatory actions of HU308 were compared with those of clinical treatments for uveitis ‐ dexamethasone, prednisolone and nepafenac. Transcription factors (NF‐κB, AP‐1) and inflammatory mediators (cytokines, chemokines and adhesion molecules) were measured in iris and ciliary body tissue.
Key Results
Leukocyte‐endothelium adherence was increased in iridial microvasculature between 4–6 h after LPS. HU308 reduced this effect after LPS injection and decreased pro‐inflammatory mediators: TNF‐α, IL‐1β, IL‐6, CCL5 and CXCL2. AM630 blocked the actions of HU‐308, and increased leukocyte‐endothelium adhesion. HU‐308 decreased levels of the transcription factors NF‐κB and AP‐1, while AM630 increased levels of NF‐κB. Topical treatments with dexamethasone, prednisolone or nepafenac, failed to alter leukocyte adhesion or mitigate LPS‐induced increases in inflammatory mediators during the 6 h of EIU.
Conclusion and Implications
Activation of CB2 receptors was anti‐inflammatory in a model of acute EIU and involved a reduction in NF‐κB, AP‐1 and inflammatory mediators. CB2 receptors may be promising drug targets for the development of novel ocular anti‐inflammatory agents.
Linked Articles
This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐6
Background and Purpose
We sought to understand why (−)‐cannabidiol (CBD) and (−)‐cannabidiol‐dimethylheptyl (CBD‐DMH) exhibit distinct pharmacology, despite near identical structures.
Experimental ...Approach
HEK293A cells expressing either human type 1 cannabinoid (CB1) receptors or CB2 receptors were treated with CBD or CBD‐DMH with or without the CB1 and CB2 receptor agonist CP55,940, CB1 receptor allosteric modulator Org27569 or CB2 receptor inverse agonist SR144528. Ligand binding, cAMP levels and βarrestin1 recruitment were measured. CBD and CBD‐DMH binding was simulated with models of human CB1 or CB2 receptors, based on the recently published crystal structures of agonist‐bound (5XRA) or antagonist‐bound (5TGZ) human CB1 receptors.
Key Results
At CB1 receptors, CBD was a negative allosteric modulator (NAM), and CBD‐DMH was a mixed agonist/positive allosteric modulator. CBD and Org27569 shared multiple interacting residues in the antagonist‐bound model of CB1 receptors (5TGZ) but shared a binding site with CP55,940 in the agonist‐bound model of CB1 receptors (5XRA). The binding site for CBD‐DMH in the CB1 receptor models overlapped with CP55,940 and Org27569. At CB2 receptors, CBD was a partial agonist, and CBD‐DMH was a positive allosteric modulator of cAMP modulation but a NAM of βarrestin1 recruitment. CBD, CP55,940 and SR144528 shared a binding site in the CB2 receptor models that was separate from CBD‐DMH.
Conclusion and Implications
The pharmacological activity of CBD and CBD‐DMH in HEK293A cells and their modelled binding sites at CB1 and CB2 receptors may explain their in vivo effects and illuminates the difficulties associated with the development of allosteric modulators for CB1 and CB2 receptors.
Linked Articles
This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc
An adeno-associated viral vector was used to introduce a
FIX
gene with enhanced biologic activity in 10 participants with hemophilia B. The annualized bleeding rate was 11.1 events per year before ...therapy versus 0.4 afterward. Steady-state factor IX levels were 33.7% of normal.
Abstract
We describe data release 3 (DR3) of the Galaxy And Mass Assembly (GAMA) survey. The GAMA survey is a spectroscopic redshift and multiwavelength photometric survey in three equatorial regions ...each of 60.0 deg2 (G09, G12, and G15), and two southern regions of 55.7 deg2 (G02) and 50.6 deg2 (G23). DR3 consists of: the first release of data covering the G02 region and of data on H-ATLAS (Herschel – Astrophysical Terahertz Large Area Survey) sources in the equatorial regions; and updates to data on sources released in DR2. DR3 includes 154 809 sources with secure redshifts across four regions. A subset of the G02 region is 95.5 per cent redshift complete to r < 19.8 mag over an area of 19.5 deg2, with 20 086 galaxy redshifts, that overlaps substantially with the XXL survey (X-ray) and VIPERS (redshift survey). In the equatorial regions, the main survey has even higher completeness (98.5 per cent), and spectra for about 75 per cent of H-ATLAS filler targets were also obtained. This filler sample extends spectroscopic redshifts, for probable optical counterparts to H-ATLAS submillimetre sources, to 0.8 mag deeper (r < 20.6 mag) than the GAMA main survey. There are 25 814 galaxy redshifts for H-ATLAS sources from the GAMA main or filler surveys. GAMA DR3 is available at the survey website (www.gama-survey.org/dr3/).
The coronavirus disease 2019 (COVID-19) pandemic and antimicrobial resistance (AMR) are parallel and interacting health emergencies that provide the opportunity for mutual learning. As their measures ...and consequences are comparable, the COVID-19 pandemic helps to illustrate the potential long-term impact of AMR, which is less acute but not less crucial. They may also impact each other as there is a push to use existing antimicrobials to treat critically ill COVID-19 patients in the absence of specific treatments. Attempts to manage the spread of COVID-19 may also lead to a slowdown in AMR. Understanding how COVID-19 affects AMR trends and what we can expect if these trends remain the same or worsen will help us to plan the next steps for tackling AMR. Researchers should start collecting data to measure the impact of current COVID-19 policies and programs on AMR.
The diathesis-stress theory for depression states that the effects of stress on the depression risk are dependent on the diathesis or vulnerability, implying multiplicative interactive effects on the ...liability scale. We used polygenic risk scores for major depressive disorder (MDD) calculated from the results of the most recent analysis from the Psychiatric Genomics Consortium as a direct measure of the vulnerability for depression in a sample of 5221 individuals from 3083 families. In the same we also had measures of stressful life events and social support and a depression symptom score, as well as DSM-IV MDD diagnoses for most individuals. In order to estimate the variance in depression explained by the genetic vulnerability, the stressors and their interactions, we fitted linear mixed models controlling for relatedness for the whole sample as well as stratified by sex. We show a significant interaction of the polygenic risk scores with personal life events (0.12% of variance explained, P-value=0.0076) contributing positively to the risk of depression. Additionally, our results suggest possible differences in the aetiology of depression between women and men. In conclusion, our findings point to an extra risk for individuals with combined vulnerability and high number of reported personal life events beyond what would be expected from the additive contributions of these factors to the liability for depression, supporting the multiplicative diathesis-stress model for this disease.
This paper is the second in a pair of papers presenting data release 1 (DR1) of the Herschel Astrophysical Terahertz Large Area Survey (H-ATLAS), the largest single open-time key project carried out ...with the Herschel
Space Observatory. The H-ATLAS is a wide-area imaging survey carried out in five photometric bands at 100, 160, 250, 350 and 500 μm covering a total area of 600 deg2. In this paper, we describe the identification of optical counterparts to submillimetre sources in DR1, comprising an area of 161 deg2 over three equatorial fields of roughly 12 × 4.5 deg centred at 9h, 12h and 14
${^{\rm h}_{.}}$
5, respectively. Of all the H-ATLAS fields, the equatorial regions benefit from the greatest overlap with current multi-wavelength surveys spanning ultraviolet (UV) to mid-infrared regimes, as well as extensive spectroscopic coverage. We use a likelihood ratio technique to identify Sloan Digital Sky Survey counterparts at r < 22.4 for 250-μm-selected sources detected at ≥4σ (≈28 mJy). We find ‘reliable’ counterparts (reliability R ≥ 0.8) for 44 835 sources (39 per cent), with an estimated completeness of 73.0 per cent and contamination rate of 4.7 per cent. Using redshifts and multi-wavelength photometry from GAMA and other public catalogues, we show that H-ATLAS-selected galaxies at z < 0.5 span a wide range of optical colours, total infrared (IR) luminosities and IR/UV ratios, with no strong disposition towards mid-IR-classified active galactic nuclei in comparison with optical selection. The data described herein, together with all maps and catalogues described in the companion paper, are available from the H-ATLAS website at www.h-atlas.org.
PDF
