Turning Over a New Leaf: Cannabinoid and Endocannabinoid Modulation of Immune Function

Cannabis is a complex substance that harbors terpenoid-like compounds referred to as phytocannabinoids. The major psychoactive phytocannabinoid found in cannabis ∆9-tetrahydrocannabinol (THC) produces the majority of its pharmacological effects through two cannabinoid receptors, termed CB1 and CB2. The discovery of these receptors as linked functionally to distinct biological effects of THC, and the subsequent development of synthetic cannabinoids, precipitated discovery of the endogenous cannabinoid (or endocannabinoid) system. This system consists of the endogenous lipid ligands N- arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), their biosynthetic and degradative enzymes, and the CB1 and CB2 receptors that they activate. Endocannabinoids have been identified in immune cells such as monocytes, macrophages, basophils, lymphocytes, and dendritic cells and are believed to be enzymatically produced and released “on demand” in a similar fashion as the eicosanoids. It is now recognized that other phytocannabinoids such as cannabidiol (CBD) and cannabinol (CBN) can alter the functional activities of the immune system. This special edition of the Journal of Neuroimmune Pharmacology (JNIP) presents a collection of cutting edge original research and review articles on the medical implications of phytocannabinoids and the endocannabinoid system. The goal of this special edition is to provide an unbiased assessment of the state of research related to this topic from leading researchers in the field. The potential untoward effects as well as beneficial uses of marijuana, its phytocannabinoid composition, and synthesized cannabinoid analogs are discussed. In addition, the role of the endocannabinoid system and approaches to its manipulation to treat select human disease processes are addressed

Evaluation of CB1 receptor knockout mice in the Morris water maze.

ABSTRACT The endocannabinoid system has been proposed to modulate a variety of physiological processes, including those that underlie cognition. The present study tested whether this system is tonically active in learning and memory by comparing CB 1 receptor knockout mice (CB 1 Ϫ/Ϫ ) to wild-type mice (CB 1 ϩ/ϩ ) in several Morris water maze tasks. Also, the effects of three cannabinoid agonists, (WIN 55,, and methanandamide, were evaluated in a working memory procedure. Both genotypes exhibited identical acquisition rates in a fixed platform procedure; however, the CB 1 Ϫ/Ϫ mice demonstrated significant deficits in a reversal task in which the location of the hidden platform was moved to the opposite side of the tank. This phenotype difference was most likely due to an increased perseverance of the CB 1 Ϫ/Ϫ mice in that they continued to return to the original platform location, despite being repeatedly shown the new platform location. In addition, ⌬ 9 -THC (ED 50 ϭ 1.3 mg/ kg), WIN 55,212-2 (ED 50 ϭ 0.35 mg/kg), and methanandamide (ED 50 ϭ 3.2 mg/kg) disrupted the performance of CB 1 ϩ/ϩ mice in the working memory task at doses that did not elicit motivational or sensorimotor impairment as assessed in a cued version of the task. Furthermore, doses of each drug that were maximally disruptive in CB 1 ϩ/ϩ mice were ineffective in either N-(pip- ϩ/ϩ or CB 1 Ϫ/Ϫ mice. These results provide strong evidence that cannabinoids disrupt working memory through a CB 1 receptor mechanism of action, and suggest that the endocannabinoid system may have a role in facilitating extinction and/or forgetting processes

Age Differences in the Association of Obstructive Sleep Apnea Risk with Cognition and Quality of Life

Using a sample of 2925 stroke-free participants drawn from a national population-based study, we examined cross-sectional associations of obstructive sleep apnea risk (OSA) with cognition and quality of life and whether these vary with age, while controlling for demographics and co-morbidities. Included participants from the REasons for Geographic And Racial Differences in Stroke Study were aged 47-93. OSA risk was categorized as high or low based on responses to the Berlin Sleep Questionnaire. Cognitive function was assessed with standardized fluency and recall measures. Depressive symptoms were assessed with the four-item Center for Epidemiologic Studies Depression Scale. Health-related Quality of Life (HRQoL) was assessed with the Medical Outcomes Study Short Form-12 (SF-12). MANCOVA statistics were applied separately to the cognitive and quality of life dependent variables while accounting for potential confounders (demographics, co-morbidities). In fully adjusted models, those at high risk for OSA had significantly lower cognitive scores (Wilks’ Lambda = 0.996, F(3, 2786) = 3.31, p < .05) and lower quality of life (depressive symptoms and HRQoL) (Wilks’ Lambda = 0.989, F(3, 2786) = 10.02, p < .0001). However, some of the associations were age-dependent. Differences in cognition and quality of life between those at high and low obstructive sleep apnea risk were most pronounced during middle age, with attenuated effects after age 70

3D Multicolor Super-Resolution Imaging Offers Improved Accuracy in Neuron Tracing

The connectivity among neurons holds the key to understanding brain function. Mapping neural connectivity in brain circuits requires imaging techniques with high spatial resolution to facilitate neuron tracing and high molecular specificity to mark different cellular and molecular populations. Here, we tested a three-dimensional (3D), multicolor super-resolution imaging method, stochastic optical reconstruction microscopy (STORM), for tracing neural connectivity using cultured hippocampal neurons obtained from wild-type neonatal rat embryos as a model system. Using a membrane specific labeling approach that improves labeling density compared to cytoplasmic labeling, we imaged neural processes at 44 nm 2D and 116 nm 3D resolution as determined by considering both the localization precision of the fluorescent probes and the Nyquist criterion based on label density. Comparison with confocal images showed that, with the currently achieved resolution, we could distinguish and trace substantially more neuronal processes in the super-resolution images. The accuracy of tracing was further improved by using multicolor super-resolution imaging. The resolution obtained here was largely limited by the label density and not by the localization precision of the fluorescent probes. Therefore, higher image resolution, and thus higher tracing accuracy, can in principle be achieved by further improving the label density

Interactions between sediment microbial ecology and physical dynamics drive heterogeneity in contextually similar depositional systems

This study focuses on the interactions between sediment stability and biological and physical variables that influence the erodibility across different habitats. Sampling at short‐term temporal scales illustrated the persistence of the microphytobenthos (MPB) biomass even during periods of frequent, high physical disturbance. The role of MPB in biological stabilization along the changing sedimentary habitat was also assessed. Key biological and physical properties, such as the MPB biomass, composition, and extracellular polymeric substances, were used to predict the sediment stability (erosion threshold) of muddy and sandy habitats within close proximity to one another over multiple days, and within emersion periods. The effects of dewatering, MPB growth, and productivity were examined as well as the resilience and recovery of the MPB community after disturbance from tidal currents and waves. Canonical analysis of principal components (CAP) ordinations were used to visualize and assess the trends observed in biophysical properties between the sites, and marginal and sequential distance‐based linear models were used to identify the key properties influencing erodibility. While the particle size of the bed was important for differences between sites in the CAP analysis, it contributed less to the variability in sediment erodibility than key biological parameters. Among the biological predictors, MPB diversity explained very little variation in marginal tests but was a significant predictor in sequential tests when MPB biomass was also considered. MPB diversity and biomass were both key predictors of sediment stability, contributing 9% and 10%, respectively, to the final model compared to 2% explained by grain size

The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB1 Receptor Positive Allosteric Modulators (PAMs)

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b00252. Experimental procedures, characterization of all intermediates and target compounds, and copies of NMR spectra of compounds 1, 39-57. Molecular formula strings of target compounds are available. ACKNOWLEDGEMENTS. We gratefully thank Signal Pharma and the Canadian Institutes of Health Research Proof of Principle grants PPP-125784 and PP2-139101 for financial support and fellowship (C.C.T), NIH grants R01DA039942, P30DA033934 and VCU School of Pharmacy start-up funds (A.H.L.). We thank the EPSRC National Crystallography Service (University of Southampton) for the X-ray data collection. We are grateful to Dr Monica Sani (CNR-ICRM, Milan, Italy) and Mr Massimo Frigerio (Politecnico di Milano, Italy) for the synthesis of two tetrazole-substituted indoles (Het-1 and Het-2)Peer reviewedPostprin

Depressive symptoms in younger women and men with acute myocardial infarction:Insights from the VIRGO Study

BACKGROUND: Depression was recently recognized as a risk factor for adverse medical outcomes in patients with acute myocardial infarction (AMI). The degree to which depression is present among younger patients with an AMI, the patient profile associated with being a young AMI patient with depressive symptoms, and whether relevant sex differences exist are currently unknown. METHODS AND RESULTS: The Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study enrolled 3572 patients with AMI (67.1% women; 2:1 ratio for women to men) between 2008 and 2012 (at 103 hospitals in the United States, 24 in Spain, and 3 in Australia). Information about lifetime history of depression and depressive symptoms experienced over the past 2 weeks (Patient Health Questionnaire; a cutoff score ≥10 was used for depression screening) was collected during index AMI admission. Information on demographics, socioeconomic status, cardiovascular risk, AMI severity, perceived stress (14‐item Perceived Stress Scale), and health status (Seattle Angina Questionnaire, EuroQoL 5D) was obtained through interviews and chart abstraction. Nearly half (48%) of the women reported a lifetime history of depression versus 1 in 4 in men (24%; P<0.0001). At the time of admission for AMI, more women than men experienced depressive symptoms (39% versus 22%, P<0.0001; adjusted odds ratio 1.64; 95% CI 1.36 to 1.98). Patients with more depressive symptoms had higher levels of stress and worse quality of life (P<0.001). Depressive symptoms were more prevalent among patients with lower socioeconomic profiles (eg, lower education, uninsured) and with more cardiovascular risk factors (eg, diabetes, smoking). CONCLUSIONS: A high rate of lifetime history of depression and depressive symptoms at the time of an AMI was observed among younger women compared with men. Depressive symptoms affected those with more vulnerable socioeconomic and clinical profiles