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Endocannabinoids as Therapeutic Targets.

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Archives of Medical Research“Most of the drugs of abuse affect the brain by interacting with naturally expressed molecular receptors. Marihuana affects a series of receptors including cannabinoid receptor 1 (CB1R) and CB2R, among others. Endogenous molecules with cannabinoid activity interact with these receptors naturally. Receptors, ligands, synthesizing and degrading enzymes, as well as transporters, have been described.

This endocannabinoid system modulates behaviors and physiological processes, i.e. food intake, the sleep-waking cycle, learning and memory, motivation, and pain perception, among others. The rather broad distribution of endocannabinoids in the brain explains the different effects marihuana induces in its users. However, this very same anatomical and physiological distribution makes this system a useful target for therapeutic endeavors.

In this review, we briefly discuss the potential of small molecules that target the endocannabinoids as therapeutic tools to improve behaviors and treat illnesses. We believe that under medical supervision, endocannabinoid targets offer new advantages for patients for controlling multiple medical disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/32028095

https://www.sciencedirect.com/science/article/abs/pii/S0188440919304746?via%3Dihub

Uncovering the hidden antibiotic potential of Cannabis.

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 Go to Volume 0, Issue ja“The spread of antimicrobial resistance continues to be a priority health concern worldwide, necessitating exploration of alternative therapies.

Cannabis sativa has long been known to contain antibacterial cannabinoids, but their potential to address antibiotic resistance has only been superficially investigated.

Here, we show that cannabinoids exhibit antibacterial activity against MRSA, inhibit its ability to form biofilms and eradicate pre-formed biofilms and stationary phase cells persistent to antibiotics.

We show that the mechanism of action of cannabigerol is through targeting the cytoplasmic membrane of Gram-positive bacteria and demonstrate in vivo efficacy of cannabigerol in a murine systemic infection model caused by MRSA.

We also show that cannabinoids are effective against Gram-negative organisms whose outer membrane is permeabilized, where cannabigerol acts on the inner membrane.

Finally, we demonstrate that cannabinoids work in combination with polymyxin B against multi-drug resistant Gram-negative pathogens, revealing the broad-spectrum therapeutic potential for cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/32017534

https://pubs.acs.org/doi/10.1021/acsinfecdis.9b00419

The endocannabinoid receptors CB1 and CB2 affect the regenerative potential of adipose tissue MSCs.

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Experimental Cell Research“Human adipose tissue includes large quantities of mesenchymal stromal cells (atMSCs), which represent an abundant cell source for therapeutic applications in the field of regenerative medicine.

Adipose tissue secrets various soluble factors including endocannabinoids, and atMSCs express the cannabinoid receptors CB1 and CB2. This indicates that adipose tissue possesses an endocannabinoid system (ECS). The ECS is also ascribed great significance for wound repair, e.g. by modulating inflammation. However, the exact effects of CB1/CB2 activation in human atMSCs have not been investigated, yet.

In the present study, we stimulated human atMSCs with increasing concentrations (1-30 μM) of the unspecific cannabinoid receptor ligand WIN55,212-2 and the specific CB2 agonist JWH-133, either alone or co-applied with the receptor antagonist Rimonabant (CB1) or AM 630 (CB2). We investigated the effects on metabolic activity, cell number, differentiation and cytokine release, which are important processes during tissue regeneration.

WIN decreased metabolic activity and cell number, which was reversed by Rimonabant. This suggests a CB1 dependent mechanism, whereas the number of atMSCs was increased after CB2 ligation. WIN and JWH increased the release of VEGF, TGF-β1 and HGF. Adipogenesis was enhanced by WIN, which could be reversed by blocking CB1. There was no effect on osteogenesis, and only WIN increased chondrogenic differentiation.

Our results indicate that definite activation of the cannabinoid receptors exerted different effects in atMSCs, which could be of specific value in cell-based therapy for wound regeneration.”

https://www.ncbi.nlm.nih.gov/pubmed/32006556

https://www.sciencedirect.com/science/article/abs/pii/S001448272030080X?via%3Dihub

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Organophosphate agent induces ADHD-like behaviors via inhibition of brain endocannabinoid-hydrolyzing enzyme(s) in adolescent male rats.

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 Go to Volume 0, Issue ja“Anticholinergic organophosphate (OP) agents act on the diverse serine hydrolases, thereby revealing unexpected biological effects. Epidemiological studies indicate a relationship between OP exposure and development of attention-deficit/hyperactivity disorder (ADHD)-like symptoms, whereas no plausible mechanism for the OP-induced ADHD has been established.

The present investigation employs ethyl octylphosphonofluoridate (EOPF) as an OP-probe which is an extremely potent inhibitor of endocannabinoid (EC, anandamide and 2-arachidonoylglycerol)-hydrolyzing enzymes: i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

Ex vivo experiment shows that EOPF treatment decreases FAAH and MAGL activities and conversely increases EC levels in rat brain. Subsequently, EOPF (treated intraperitoneally once at 0, 1, 2, or 3 mg/kg) clearly induces ADHD-like behaviors (in elevated plus-maze test) in both Wistar and spontaneously hypertensive rats. The EOPF-induced behaviors are reduced by a concomitant administration of cannabinoid receptor inverse agonist SLV-319.

Accordingly, EC system is a feasible target for OP-caused ADHD-like behaviors in adolescent rats.”

https://www.ncbi.nlm.nih.gov/pubmed/31995978

https://pubs.acs.org/doi/abs/10.1021/acs.jafc.9b08195

Cryo-EM Structure of the Human Cannabinoid Receptor CB2-Gi Signaling Complex.

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Image result for cell journal“Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders, inflammation, and pain while avoiding psychotropic side effects mediated by CB1. The mechanisms underlying CB2 activation and signaling are poorly understood but critical for drug design. Here we report the cryo-EM structure of the human CB2-Gi signaling complex bound to the agonist WIN 55,212-2. The 3D structure reveals the binding mode of WIN 55,212-2 and structural determinants for distinguishing CB2 agonists from antagonists, which are supported by a pair of rationally designed agonist and antagonist. Further structural analyses with computational docking results uncover the differences between CB2 and CB1 in receptor activation, ligand recognition, and Gi coupling. These findings are expected to facilitate rational structure-based discovery of drugs targeting the cannabinoid system.”

https://www.ncbi.nlm.nih.gov/pubmed/32004460

https://www.cell.com/cell/fulltext/S0092-8674(20)30054-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420300544%3Fshowall%3Dtrue

Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures.

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Image result for cell journal“Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with Gi, as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.”

https://www.ncbi.nlm.nih.gov/pubmed/32004463

https://www.cell.com/cell/fulltext/S0092-8674(20)30055-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420300556%3Fshowall%3Dtrue

Marijuana use and coronary artery disease in young adults.

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Image result for plos one“This study aims to determine the frequency of coronary artery disease among young to middle aged adults presenting with chest pain who currently use marijuana as compared to nonusers.

Only 6.8% of the 146 marijuana users had evidence of coronary artery disease on coronary CT angiography. In comparison, the rate was 15.0% among the 1,274 marijuana nonusers.

A majority of marijuana users were younger than nonusers and had a lower frequency of hypertension and diabetes than nonusers.

There was no statistical difference in lipid panel values between the two groups.

CONCLUSION:

Among younger patients being evaluated for chest pain, self-reported cannabis use conferred no additional risk of coronary artery disease as detected on coronary CT angiography.”

https://www.ncbi.nlm.nih.gov/pubmed/31995626

“There is no association between marijuana use and the presence of coronary artery disease on coronary CT angiography in young to middle aged patients presenting with chest pain.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228326

Normalization of mediotemporal and prefrontal activity, and mediotemporal-striatal connectivity, may underlie antipsychotic effects of cannabidiol in psychosis.

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 Image result for cambridge university press“Recent evidence suggests that cannabidiol (CBD), a non-intoxicating ingredient present in cannabis extract, has an antipsychotic effect in people with established psychosis. However, the effect of CBD on the neurocognitive mechanisms underlying psychosis is unknown.

METHODS:

Patients with established psychosis on standard antipsychotic treatment were studied on separate days at least one week apart, to investigate the effects of a single dose of orally administered CBD (600 mg) compared to a matched placebo (PLB), using a double-blind, randomized, PLB-controlled, repeated-measures, within-subject cross-over design. Three hours after taking the study drug participants were scanned using a block design functional magnetic resonance imaging (fMRI) paradigm, while performing a verbal paired associate learning task. Fifteen psychosis patients completed both study days, 13 completed both scanning sessions. Nineteen healthy controls (HC) were also scanned using the same fMRI paradigm under identical conditions, but without any drug administration. Effects of CBD on brain activation measured using the blood oxygen level-dependent hemodynamic response fMRI signal were studied in the mediotemporal, prefrontal, and striatal regions of interest.

RESULTS:

Compared to HC, psychosis patients under PLB had altered prefrontal activation during verbal encoding, as well as altered mediotemporal and prefrontal activation and greater mediotemporal-striatal functional connectivity during verbal recall. CBD attenuated dysfunction in these regions such that activation under its influence was intermediate between the PLB condition and HC. CBD also attenuated hippocampal-striatal functional connectivity and caused trend-level symptom reduction in psychosis patients.

CONCLUSIONS:

This suggests that normalization of mediotemporal and prefrontal dysfunction and mediotemporal-striatal functional connectivity may underlie the antipsychotic effects of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/31994476

https://www.cambridge.org/core/journals/psychological-medicine/article/normalization-of-mediotemporal-and-prefrontal-activity-and-mediotemporalstriatal-connectivity-may-underlie-antipsychotic-effects-of-cannabidiol-in-psychosis/6571F47CE15D05DC50782A7BB7C00A7F

Cannabinoids for the Treatment of Chronic Pruritus: A Review.

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Journal of the American Academy of Dermatology Home“Medical marijuana is becoming widely available to patients in the U.S. and with recreational marijuana now legalized in many states, patient interest is on the rise.

The endocannabinoid system plays an important role in skin homeostasis in addition to broader effects on neurogenic responses such as pruritus and nociception, inflammation, and immune reactions. There are numerous studies of in vitro and animal models that provide insight into the possible mechanisms of cannabinoid modulation on pruritus, with the most evidence behind neuronal modulation of both peripheral itch fibers and centrally-acting cannabinoid receptors.

In addition, human studies, while limited due to differences in cannabinoids used, disease models, and delivery method, have consistently shown significant reductions in both scratching and symptomatology in chronic pruritus. Clinical studies that have shown reduction in pruritus in several dermatologic (atopic dermatitis, psoriasis, asteatotic eczema, prurigo nodularis, allergic contact dermatitis) and systemic (uremic pruritus, cholestatic pruritus) diseases.

These preliminary human studies warrant controlled trials to confirm the benefit of cannabinoids for treatment of pruritus and to standardize treatment regimens and indications. In patients who have refractory chronic pruritus after standard therapies, cannabinoid formulations may be considered as an adjuvant therapy where it is legal.”

https://www.ncbi.nlm.nih.gov/pubmed/31987788

https://www.jaad.org/article/S0190-9622(20)30120-1/pdf

Abnormal Cannabidiol Affects Production of Pro-Inflammatory Mediators and Astrocyte Wound Closure in Primary Astrocytic-Microglial Cocultures.

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molecules-logo “Abnormal cannabidiol (abn-CBD) exerts neuroprotective effects in vivo and in vitro. In the present study, we investigated the impact of abn-CBD on the glial production of proinflammatory mediators and scar formation within in vitro models. Primary astrocytic-microglial cocultures and astrocytic cultures from neonatal C57BL/6 mice and CB2 receptor knockout mice were stimulated with lipopolysaccharide (LPS), and the concentrations of tumor necrosis factor α (TNFα), interleukin-6 (IL-6) and nitrite were determined. Furthermore, we performed a live cell microscopy-based scratch-wound assay. After LPS stimulation, TNFα, IL-6 and nitrite production was more strongly increased in cocultures than in isolated astrocytes. Abn-CBD treatment attenuated the LPS-induced production of TNFα and nitrite in cocultures, while IL-6 production remained unaltered. In isolated astrocytes, only LPS-induced TNFα production was reduced by abn-CBD. Similar effects were observed after abn-CBD application in cocultures of CB2 knockout mice. Interestingly, LPS-induced TNFα and nitrite levels were far lower in CB2 knockout cultures compared to wildtypes, while IL-6 levels did not differ. In the scratch-wound assay, treatment with abn-CBD decelerated wound closure when microglial cells were present. Our data shows a differential role of abn-CBD for modulation of glial inflammation and astrocytic scar formation. These findings provide new explanations for mechanisms behind the neuroprotective potential of abn-CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/31979350

https://www.mdpi.com/1420-3049/25/3/496