Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild to moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no available treatments to ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with sub-chronic (10 d) JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiac function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS.

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Long-term decreased cannabinoid type-1 receptor activity restores specific neurological phenotypes in the Ts65Dn mouse model of Down syndrome

10.1101/2021.11.22.469296 ◽

2021 ◽

Author(s):

Anna Vazquez-Oliver ◽

Silvia Perez-Garcia ◽

Nieves Pizarro ◽

Laura Molina-Porcel ◽

Rafael de la Torre ◽

...

Keyword(s):

Down Syndrome ◽

Side Effects ◽

Mouse Model ◽

Neurological Deficits ◽

Wild Type ◽

Male And Female ◽

Cannabinoid Type 1 Receptor ◽

Cognitive Improvement

Intellectual disability is the most prevalent and limiting hallmark of Down syndrome (DS), without any pharmacological treatment available. Neurodegeneration and neuroinflammation are relevant neurological features of DS reaching to early development of Alzheimer s disease. Preclinical evidence suggests that the endocannabinoid system, an important neuromodulator on cognition and neuroinflammation, could act as beneficial target in DS. Indeed, cannabinoid type-1 receptor (CB1R) activity was enhanced in the hippocampus of young-adult trisomic Ts65Dn mice, a well-characterized surrogate model of DS. In previous studies, inhibition of CB1R, was able to restore key neurological deficits in this mouse model. To determine the possible clinical relevance of this target, it is mandatory to evaluate the long-term consequences of attenuated CB1R activity and to minimize the possible side-effects associated to this mechanism. We found that CB1R expression was significantly enhanced in the hippocampus brains of aged DS subjects. Similarly, middle-aged trisomic mice showed enhanced CB1R expression. Long-term oral administration of a low dose of the CB1R specific antagonist rimonabant was administered to male and female Ts65Dn trisomic and wild-type mice from the time of weaning to 10 months, an age when signs of neurodegeneration have been described in the model. CB1R inhibition resulted in significant cognitive improvement in novel object-recognition memory in trisomic male and female mice, reaching a similar performance to that of wild-type littermates. Interestingly, this long-term rimonabant treatment modify locomotor activity, anxiety-like behavior, body weight or survival rates. Brain analysis at 10 months of age revealed noradrenergic and cholinergic neurodegeneration signs in trisomic mice that were not modified by the treatment, although the alterations in hippocampal microglia morphology shown by vehicle-treated trisomic mice was normalized in trisomic mice exposed to rimonabant. Altogether, our results demonstrate a sustained pro-cognitive effect of CB1R inhibition at doses that do not produce major side effects that could be associated to an anti-inflammatory action, suggesting a potential interest in this target of to preserve cognitive functionality in DS.

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Rapid upregulation and clearance of distinct circulating microRNAs after prolonged aerobic exercise

Journal of Applied Physiology ◽

10.1152/japplphysiol.01141.2013 ◽

2014 ◽

Vol 116 (5) ◽

pp. 522-531 ◽

Cited By ~ 92

Author(s):

Aaron L. Baggish ◽

Joseph Park ◽

Pil-Ki Min ◽

Stephanie Isaacs ◽

Beth A. Parker ◽

...

Keyword(s):

Aerobic Exercise ◽

Cardiac Tissue ◽

Tissue Injury ◽

Expression Patterns ◽

Plasma Concentrations ◽

Tissue Type ◽

Protein Biomarkers ◽

Rna Molecules ◽

Exercise Induced ◽

The Impact

Short nonprotein coding RNA molecules, known as microRNAs (miRNAs), are intracellular mediators of adaptive processes, including muscle hypertrophy, contractile force generation, and inflammation. During basal conditions and tissue injury, miRNAs are released into the bloodstream as “circulating” miRNAs (c-miRNAs). To date, the impact of extended-duration, submaximal aerobic exercise on plasma concentrations of c-miRNAs remains incompletely characterized. We hypothesized that specific c-miRNAs are differentially upregulated following prolonged aerobic exercise. To test this hypothesis, we measured concentrations of c-miRNAs enriched in muscle (miR-1, miR-133a, miR-499–5p), cardiac tissue (miR-208a), and the vascular endothelium (miR-126), as well as those important in inflammation (miR-146a) in healthy male marathon runners ( N = 21) at rest, immediately after a marathon (42-km foot race), and 24 h after the race. In addition, we compared c-miRNA profiles to those of conventional protein biomarkers reflective of skeletal muscle damage, cardiac stress and necrosis, and systemic inflammation. Candidate c-miRNAs increased immediately after the marathon and declined to prerace levels or lower after 24 h of race completion. However, the magnitude of change for each c-miRNA differed, even when originating from the same tissue type. In contrast, traditional biomarkers increased after exercise but remained elevated 24 h postexercise. Thus c-miRNAs respond differentially to prolonged exercise, suggesting the existence of specific mechanisms of c-miRNA release and clearance not fully explained by generalized cellular injury. Furthermore, c-miRNA expression patterns differ in a temporal fashion from corollary conventional tissue-specific biomarkers, emphasizing the potential of c-miRNAs as unique, real-time markers of exercise-induced tissue adaptation.

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Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model

Genes ◽

10.3390/genes7090056 ◽

2016 ◽

Vol 7 (9) ◽

pp. 56 ◽

Cited By ~ 20

Author(s):

Maria Gomis-González ◽

Arnau Busquets-Garcia ◽

Carlos Matute ◽

Rafael Maldonado ◽

Susana Mato ◽

...

Keyword(s):

Mouse Model ◽

Receptor Antagonist ◽

Fragile X Syndrome ◽

Fragile X ◽

Cannabinoid Type 1 Receptor ◽

Therapeutic Doses

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Cardiac Tissue Factor Regulates Inflammation, Hypertrophy and Heart Failure in Mouse Model of Type 1 Diabetes

Diabetes ◽

10.2337/db20-0719 ◽

2021 ◽

pp. db200719

Author(s):

Mary Cibi Dasan ◽

Reddemma Sandireddy ◽

Hanumakumar Bogireddy ◽

Nicole Tee ◽

Siti Aishah Binte Abdul Ghani ◽

...

Keyword(s):

Heart Failure ◽

Type 1 Diabetes ◽

Mouse Model ◽

Tissue Factor ◽

Cardiac Tissue

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A novel mouse model of Duchenne muscular dystrophy carrying a multi-exonic Dmd deletion exhibits progressive muscular dystrophy and early-onset cardiomyopathy

Disease Models & Mechanisms ◽

10.1242/dmm.045369 ◽

2020 ◽

Vol 13 (9) ◽

pp. dmm045369

Author(s):

Tatianna Wai Ying Wong ◽

Abdalla Ahmed ◽

Grace Yang ◽

Eleonora Maino ◽

Sydney Steiman ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Early Onset ◽

Treatment Strategies ◽

Clinical Model ◽

Life Threatening ◽

Cardiac Muscles ◽

Almost All ◽

The Impact

ABSTRACTDuchenne muscular dystrophy (DMD) is a life-threatening neuromuscular disease caused by the lack of dystrophin, resulting in progressive muscle wasting and locomotor dysfunctions. By adulthood, almost all patients also develop cardiomyopathy, which is the primary cause of death in DMD. Although there has been extensive effort in creating animal models to study treatment strategies for DMD, most fail to recapitulate the complete skeletal and cardiac disease manifestations that are presented in affected patients. Here, we generated a mouse model mirroring a patient deletion mutation of exons 52-54 (Dmd Δ52-54). The Dmd Δ52-54 mutation led to the absence of dystrophin, resulting in progressive muscle deterioration with weakened muscle strength. Moreover, Dmd Δ52-54 mice present with early-onset hypertrophic cardiomyopathy, which is absent in current pre-clinical dystrophin-deficient mouse models. Therefore, Dmd Δ52-54 presents itself as an excellent pre-clinical model to evaluate the impact on skeletal and cardiac muscles for both mutation-dependent and -independent approaches.

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Impact of Cannabinoid Type 1 Receptor Modulation on Risky Decision-Making

10.1101/2020.03.13.990721 ◽

2020 ◽

Author(s):

Timothy G. Freels ◽

Anna E. Liley ◽

Daniel B. K. Gabriel ◽

Nicholas W. Simon

Keyword(s):

Decision Making ◽

Risk Taking ◽

Neural Substrates ◽

Risky Decision Making ◽

Risky Decision ◽

Cannabinoid Type 1 Receptor ◽

Receptor Modulation ◽

Choice Latency ◽

The Impact

ABSTRACTRecent changes in policy regarding cannabis in the U.S. have been accompanied by an increase in the prevalence of cannabis use and a reduction in the perceived harms associated with consumption. However, little is understood regarding the effects of cannabinoids on cognitive processes. Given that deficient risk-taking is commonly observed in individuals suffering from substance use disorders (SUDs), we assessed the impact of manipulating cannabinoid type 1 receptors (CB1Rs; the primary target for Δ9-tetrahydrocannabinol in the brain) on punishment-based risk-taking using the risky decision-making task (RDT) in male Long-Evans rats. The RDT measures preference for small, safe rewards over large, risky rewards associated with an escalating chance of foot shock. Systemic bidirectional CB1R manipulation with a CB1R agonist, CB1R antagonist, and FAAH inhibitor (which increases overall endocannabinoid tone) did not alter overt risk-taking in the RDT. Interestingly, direct CB1R agonism, but not indirect CB1R stimulation or CB1R blockade, resulted in reduction in latency to make risky choices while not altering safe choice latency. Our findings suggest that CB1R activation expedites engagement in punishment based risk-taking without affecting overall preference for risky vs. safe options. This indicates that risk preference and rate of deliberation for risk-taking are influenced by distinct neural substrates, an important consideration for development of precise treatments targeting the aberrant risk-taking typical of SUD symptomology.

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Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00317.2013 ◽

2014 ◽

Vol 307 (2) ◽

pp. G140-G148 ◽

Cited By ~ 15

Author(s):

Luan C. Koay ◽

Rachael J. Rigby ◽

Karen L. Wright

Keyword(s):

Protein Expression ◽

Intestinal Epithelium ◽

Intestinal Inflammation ◽

Cytokine Signaling ◽

Dependent Manner ◽

Suppressor Of Cytokine Signaling ◽

Cannabinoid Type 1 Receptor ◽

The Impact ◽

Socs3 Protein

Autophagy is a catabolic process involved in homeostatic and regulated cellular protein recycling and degradation via the lysosomal degradation pathway. Emerging data associate impaired autophagy, increased activity in the endocannabinoid system, and upregulation of suppressor of cytokine signaling-3 (SOCS3) protein expression during intestinal inflammation. We have investigated whether these three processes are linked. By assessing the impact of the phytocannabinoid cannabidiol (CBD), the synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA), and the endocannabinoid N-arachidonoylethanolamine (AEA) on autophagosome formation, we explored whether these actions were responsible for cyclic SOCS3 protein levels. Our findings show that all three cannabinoids induce autophagy in a dose-dependent manner in fully differentiated Caco-2 cells, a model of mature intestinal epithelium. ACEA and AEA induced canonical autophagy, which was cannabinoid type 1 receptor-mediated. In contrast, CBD was able to bypass the cannabinoid type 1 receptor and the canonical pathway to induce autophagy, albeit to a lesser extent. Functionally, all three cannabinoids reduced SOCS3 protein expression, which was reversed by blocking early and late autophagy. In conclusion, the regulatory protein SOCS3 is regulated by autophagy, and cannabinoids play a role in this process, which could be important when therapeutic applications for the cannabinoids in inflammatory conditions are considered.

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The impact of SGLT2 inhibitors, compared with insulin, on diabetic bone disease in a mouse model of type 1 diabetes

Bone ◽

10.1016/j.bone.2016.10.026 ◽

2017 ◽

Vol 94 ◽

pp. 141-151 ◽

Cited By ~ 28

Author(s):

Kathryn M. Thrailkill ◽

Jeffry S. Nyman ◽

R. Clay Bunn ◽

Sasidhar Uppuganti ◽

Katherine L. Thompson ◽

...

Keyword(s):

Type 1 Diabetes ◽

Mouse Model ◽

Bone Disease ◽

Sglt2 Inhibitors ◽

The Impact

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Proteomic Studies Reveal Coordinated Changes in T-Cell Expression Patterns upon Infection with Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.01819-07 ◽

2008 ◽

Vol 82 (9) ◽

pp. 4320-4330 ◽

Cited By ~ 62

Author(s):

Jeffrey H. Ringrose ◽

Rienk E. Jeeninga ◽

Ben Berkhout ◽

Dave Speijer

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Intracellular Transport ◽

Expression Patterns ◽

Immunodeficiency Virus ◽

Cell Expression ◽

The Impact ◽

Hiv 1

ABSTRACT We performed an extensive two-dimensional differential in-gel electrophoresis proteomic analysis of the cellular changes in human T cells upon human immunodeficiency virus type 1 (HIV-1) infection. We detected 2,000 protein spots, 15% of which were differentially expressed at peak infection. A total of 93 proteins that changed in relative abundance were identified. Of these, 27 were found to be significantly downregulated and 66 were upregulated at peak HIV infection. Early in infection, only a small group of proteins was changed. A clear and consistent program of metabolic rerouting could be seen, in which glycolysis was downregulated and mitochondrial oxidation enhanced. Proteins that participate in apoptotic signaling were also significantly influenced. Apart from these changes, the virus also strongly influenced levels of proteins involved in intracellular transport. These and other results are discussed in light of previous microarray and proteomic studies regarding the impact of HIV-1 infection on cellular mRNA and protein content.

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The cloning and characterization of the cannabinoid type 1 receptor

10.1093/med/9780198834359.003.0025 ◽

2018 ◽

Author(s):

Mary E. Abood ◽

Thomas Gamage

Keyword(s):

Chronic Pain ◽

Cannabinoid Receptor ◽

Functional Characterization ◽

Endocannabinoid System ◽

Cb1 Receptor ◽

Cannabinoid Type 1 Receptor ◽

Endogenous Cannabinoid ◽

Endogenous Cannabinoid System

The cloning and characterization of the first cannabinoid receptor (now known as the cannabinoid type 1 (CB1) receptor) by Matsuda et al. in the landmark paper discussed in this chapter was a seminal discovery in 1990. While the analgesic properties of marijuana had been known for thousands of years, the mechanisms through which marijuana produces analgesia were not understood. The identification and functional characterization of the CB1 receptor led to the discovery of an endogenous cannabinoid system (the endocannabinoid system), which has now been shown to be important not only for acute and chronic pain states, but also for a whole host of physiological and pathophysiological disorders.

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