Structural and Functional Insights into Cannabinoid Receptors

 Trends in Pharmacological Sciences (@TrendsinPharma) | Twitter“Cannabinoid receptors type 1 (CB1) and 2 (CB2) are widely expressed in the human body, and are attractive drug targets in the prevention and management of central nervous system (CNS) and immune system dysfunction, respectively. Recent breakthroughs in the structural elucidation of cannabinoid receptors and their signaling complexes with G proteins, provide the important molecular basis of ligand-receptor interactions, activation and signaling mechanism, which will facilitate the next-generation drug design and the precise modulation of the endocannabinoid system. Here, we provide an overview on the structural features of cannabinoid receptors in different functional states and the diverse ligand binding modes. The major challenges and new strategies for future therapeutic applications targeting the endocannabinoid system (ECS) are also discussed.”

https://pubmed.ncbi.nlm.nih.gov/32739033/

“Cannabinoid receptors as key components of the endocannabinoid system are involved in regulating a variety of physiological and pathological activities, and their ligands are regarded as potential drug candidates for the treatment of many diseases.”

https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(20)30146-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0165614720301462%3Fshowall%3Dtrue

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Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products

ijms-logo “Cannabinoid receptors (CB1 and CB2), as part of the endocannabinoid system, play a critical role in numerous human physiological and pathological conditions. Thus, considerable efforts have been made to develop ligands for CB1 and CB2, resulting in hundreds of phyto- and synthetic cannabinoids which have shown varying affinities relevant for the treatment of various diseases. However, only a few of these ligands are clinically used.

Recently, more detailed structural information for cannabinoid receptors was revealed thanks to the powerfulness of cryo-electron microscopy, which now can accelerate structure-based drug discovery. At the same time, novel peptide-type cannabinoids from animal sources have arrived at the scene, with their potential in vivo therapeutic effects in relation to cannabinoid receptors.

From a natural products perspective, it is expected that more novel cannabinoids will be discovered and forecasted as promising drug leads from diverse natural sources and species, such as animal venoms which constitute a true pharmacopeia of toxins modulating diverse targets, including voltage- and ligand-gated ion channels, G protein-coupled receptors such as CB1 and CB2, with astonishing affinity and selectivity. Therefore, it is believed that discovering novel cannabinoids starting from studying the biodiversity of the species living on planet earth is an uncharted territory.”

https://pubmed.ncbi.nlm.nih.gov/32709050/

https://www.mdpi.com/1422-0067/21/14/5064

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Cholesterol regulates cannabinoid analgesia through glycine receptors

Neuropharmacology “Cholesterol plays vital roles in many central physiological and pathological processes. As a key component in the cell membrane, cholesterol can regulate a variety of ion channels, including ligand-gated ion channels (LGICs). However, relatively little is known about the molecular detail and in vivo consequence of cholesterol-LGIC interaction. Here, we reveal that membrane cholesterol depletion significantly inhibits the potentiating effects of dehydroxylcannabidiol (DH-CBD) on glycine-activated currents (IGly) in HEK 293T cells expressing α1/α3 glycine receptors (GlyRs). Simvastatin considerably decreases cholesterol levels and DH-CBD-induced potentiation of IGly in the spinal cord of mice. Simvastatin also significantly decreases DH-CBD analgesia in acute and chronic pain of mice. The cholesterol levels in the dorsal horn of spinal cord, measured by mass spectrometry imaging, are specifically correlated with cannabinoid potentiation of spinal GlyRs and cannabinoid-induced analgesia. These findings suggest that spinal cholesterol is critical for the efficacy of glycinergic cannabinoid-induced analgesia.”

https://pubmed.ncbi.nlm.nih.gov/32712277/

https://www.sciencedirect.com/science/article/abs/pii/S0028390820303105?via%3Dihub

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Cannabinoid-profiled agents improve cell survival via reduction of oxidative stress and inflammation, and Nrf2 activation in a toxic model combining hyperglycemia+Aβ 1-42 peptide in rat hippocampal neurons

Neurochemistry International “Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder linked to various converging toxic mechanisms. Evidence suggests that hyperglycemia induces oxidative stress, mitochondrial dysfunction, inflammation and excitotoxicity, all of which play important roles in the onset and progression of AD pathogenesis.

The endocannabinoid system (ECS) orchestrates major physiological responses, including neuronal plasticity, neuroprotection, and redox homeostasis, to name a few. The multi-targeted effectiveness of the ECS emerges as a potential approach to treat AD.

Here we characterized the protective properties of the endocannabinoids arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), the synthetic cannabinoids CP 55-940 and WIN 55,212-2, and the fatty acid amide hydrolase (FAAH) inhibitor URB597, on a combined hyperglycemia+oligomeric amyloid β peptide (Aβ1-42) neurotoxic model in primary hippocampal neurons which exhibit several AD features.

All agents tested preserved cell viability and stimulated mitochondrial membrane potential, while reducing all the evaluated toxic endpoints in a differential manner, with URB597 showing the highest efficacy. The neuroprotective efficacy of all cannabinoid agents, except for URB597, led to partial recruitment of specific antioxidant activity and Nrf2 pathway regulation.

Our results support the neuroprotective potential of these agents at low concentrations against the damaging effects of GLU+Aβ1-42, affording new potential modalities for the design of AD therapies.”

https://pubmed.ncbi.nlm.nih.gov/32781098/

“All cannabinoid agents prevented the GLU + Aβ1-42 toxicity in a differential manner. All cannabinoid agents recruited Nrf2 signaling to protect cells.”

https://www.sciencedirect.com/science/article/abs/pii/S0197018620302084?via%3Dihub

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Cannabis and the Gastrointestinal Tract

“Cannabis has been used for its medicinal purposes since ancient times. Its consumption leads to the activation of Cannabis receptors CB1 and CB2 that, through specific mechanisms can lead to modulation and progression of inflammation or repair. The novel findings are linked to the medical use of Cannabis in gastrointestinal (GI) system.

Purpose: The objective of the present paper is to elucidate the role of Cannabis consumption in GI system. An additional aim is to review the information on the function of Cannabis in non-alcoholic fatty liver disease (NAFLD).

Methods and results: This review summarizes the recent findings on the role of cannabinoid receptors, their synthetic or natural ligands, as well as their metabolizing enzymes in normal GI function and its disorders, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and possible adverse events. The synergism or antagonism between Cannabis’ active ingredients and the “entourage” plays a role in the efficacy of various strains. Some elements of Cannabis may alter disease severity as over-activation of Cannabis receptors CB1 and CB2 can lead to changes of the commensal gut flora. The endocannabinoid system (ECS) contributes to gut homeostasis. The ability of ECS to modulate inflammatory responses demonstrates the capacity of ECS to preserve gastrointestinal (GI) function. Alterations of the ECS may predispose patients to pathologic disorders, including IBD. Clinical studies in IBD demonstrate that subjects benefit from Cannabis consumption as seen through a reduction of the IBD-inflammation, as well as through a decreased need for other medication. NAFLD is characterized by fat accumulation in the liver. The occurrence of inflammation in NAFLD leads to non-alcoholic-steatohepatitis (NASH). The use of Cannabis might reduce liver inflammation.

Conclusions: With limited evidence of efficacy and safety of Cannabis in IBD, IBS, and NAFLD, randomized controlled studies are required to examine its therapeutic efficacy.”

https://pubmed.ncbi.nlm.nih.gov/32762830/

https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/31242

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Cannabis use is associated with a lower risk of diabetes in chronic hepatitis C-infected patients (ANRS CO22 Hepather cohort)

 Medscape | J Viral Hepat - Content Listing“Chronic hepatitis C virus (HCV) infection is a risk factor of insulin resistance, and HCV-infected patients are at a high risk of developing diabetes.

In the general population, research has shown the potential benefit of cannabis use for the prevention of diabetes and related metabolic disorders.

We aimed to test whether cannabis use is associated with a lower risk of diabetes in chronic HCV-infected patients.

After multivariable adjustment, current (AOR [95%CI]: 0.49 [0.38-0.63]) and former (0.81 [0.67-0.98], p<.001) cannabis use were both associated with a reduced odds of diabetes. Conversely, male gender, tobacco use, elevated BMI, poverty, being a migrant and advanced fibrosis were associated with increased odds of diabetes. The association between cannabis use and diabetes was maintained in the stratified analysis.

In this large cross-sectional study of chronic HCV-infected patients, cannabis use was associated with a lower risk of diabetes independently of clinical and socio-behavioral factors. Further studies are needed to elucidate a potential causal link and shed light on cannabis compounds and mechanisms involved in this relationship.”

https://pubmed.ncbi.nlm.nih.gov/32810343/

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Flavonoid and cannabinoid impact on the ocular surface

 Media Kit - Current Opinion in Allergy and Clinical Immunology | Lippincott  Audience Solutions | Wolters Kluwer“Purpose of review: To evaluate the impact of flavonoids and cannabinoids as anti-inflammatory and antiallergic treatments on the anterior surface of the eye.

Recent findings: Allergic conjunctivitis and dry eye syndrome are common ocular surface diseases that have been treated with traditional pharmacological measures, e.g. corticosteroids, antihistamines. Given the side-effect profiles of these medications and the growing interest in complementary treatment modalities as part of integrative medical interventions, well known flavonoids, such as quercetin and catechin, are under investigation for topical and systemic application methods for relief. As flavonoid derivatives, pycnogenol and epigallocatechin gallate have alleviated dry eye symptoms, including lacrimal gland inflammation, tear secretion, and the stability of the tear film. Research on ocular cannabinoid receptors and response to synthetic cannabinoids are also being considered for therapy of anterior ocular disorders. The expansion of herbal formulations provides a framework for future treatment regimens for ocular surface disorders.

Summary: Flavonoids and cannabinoids show promise as potential complementary treatment for allergic diseases because of their anti-inflammatory and antiallergic properties. Several studies implementing ocular and systemic application of these compounds show potential in becoming adjuvant treatment strategies for improving quality of life while also managing ocular surface disease processes.”

https://pubmed.ncbi.nlm.nih.gov/32796166/

https://journals.lww.com/co-allergy/Abstract/2020/10000/Flavonoid_and_cannabinoid_impact_on_the_ocular.11.aspx

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Substance use disorders and risk of severe maternal morbidity in the United States

Drug and Alcohol Dependence “The contribution of substance use disorders to the burden of severe maternal morbidity in the United States is poorly understood. The objective was to estimate the independent association between substance use disorders during pregnancy and risk of severe maternal morbidity.

Results: Pregnant women with an opioid use disorder had an increased risk of severe maternal morbidity compared with women without an opioid use disorder (18-34 years: aOR: 1.51; 95 % CI: 1.41,1.61, >34 years: aOR: 1.17; 95 % CI: 1.00,1.38). Compared with their counterparts without stimulant use disorders, pregnant women with a simulant use disorder (amphetamines, cocaine) had an increased risk of severe maternal morbidity (18-34 years: aOR: 1.92; 95 % CI: 1.80,2.0, >34 years: aOR: 1.85; 95 % CI: 1.66,2.06). Cannabis use disorders were not associated with an increased risk of severe maternal morbidity.

Conclusion: Substance use disorders during pregnancy, particularly opioids, amphetamines, and cocaine use disorders, may contribute to severe maternal morbidity in the United States.”

https://pubmed.ncbi.nlm.nih.gov/32846369/

“Cannabis use disorder was not associated with increased risk of severe maternal morbidity.”

https://www.sciencedirect.com/science/article/abs/pii/S0376871620304014?via%3Dihub

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Cannabis Improves Obsessive-Compulsive Disorder-Case Report and Review of the Literature

Archive of "Frontiers in Psychiatry". “Although several lines of evidence support the hypothesis of a dysregulation of serotoninergic neurotransmission in the pathophysiology of obsessive-compulsive disorder (OCD), there is also evidence for an involvement of other pathways such as the GABAergic, glutamatergic, and dopaminergic systems.

Only recently, data obtained from a small number of animal studies alternatively suggested an involvement of the endocannabinoid system in the pathophysiology of OCD reporting beneficial effects in OCD-like behavior after use of substances that stimulate the endocannabinoid system.

In humans, until today, only two case reports are available reporting successful treatment with dronabinol (tetrahydrocannabinol, THC), an agonist at central cannabinoid CB1 receptors, in patients with otherwise treatment refractory OCD. In addition, data obtained from a small open uncontrolled trial using the THC analogue nabilone suggest that the combination of nabilone plus exposure-based psychotherapy is more effective than each treatment alone.

These reports are in line with data from a limited number of case studies and small controlled trials in patients with Tourette syndrome (TS), a chronic motor and vocal tic disorder often associated with comorbid obsessive compulsive behavior (OCB), reporting not only an improvement of tics, but also of comorbid OCB after use of different kinds of cannabis-based medicines including THC, cannabis extracts, and flowers.

Here we present the case of a 22-year-old male patient, who suffered from severe OCD since childhood and significantly improved after treatment with medicinal cannabis with markedly reduced OCD and depression resulting in a considerable improvement of quality of life. In addition, we give a review of current literature on the effects of cannabinoids in animal models and patients with OCD and suggest a cannabinoid hypothesis of OCD.”

https://pubmed.ncbi.nlm.nih.gov/32848902/

https://www.frontiersin.org/articles/10.3389/fpsyt.2020.00681/full

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Rapid Antibacterial Activity of Cannabichromenic Acid against Methicillin-Resistant Staphylococcus aureus

antibiotics-logo “Methicillin-resistant Staphylococcus aureus (MRSA) has proven to be an imminent threat to public health, intensifying the need for novel therapeutics.

Previous evidence suggests that cannabinoids harbour potent antibacterial activity.

In this study, a group of previously inaccessible phytocannabinoids and synthetic analogues were examined for potential antibacterial activity.

The minimum inhibitory concentrations and dynamics of bacterial inhibition, determined through resazurin reduction and time-kill assays, revealed the potent antibacterial activity of the phytocannabinoids against gram-positive antibiotic-resistant bacterial species, including MRSA.

One phytocannabinoid, cannabichromenic acid (CBCA), demonstrated faster and more potent bactericidal activity than vancomycin, the currently recommended antibiotic for the treatment of MRSA infections. Such bactericidal activity was sustained against low-and high-dose inoculums as well as exponential- and stationary-phase MRSA cells. Further, mammalian cell viability was maintained in the presence of CBCA. Finally, microscopic evaluation suggests that CBCA may function through the degradation of the bacterial lipid membrane and alteration of the bacterial nucleoid.

The results of the current study provide encouraging evidence that cannabinoids may serve as a previously unrecognised resource for the generation of novel antibiotics active against MRSA.”

https://pubmed.ncbi.nlm.nih.gov/32824356/

https://www.mdpi.com/2079-6382/9/8/523

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