Cannabinoid Receptor Type 2: A Possible Target in SARS-CoV-2 (CoV-19) Infection?

ijms-logo“In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.”

https://pubmed.ncbi.nlm.nih.gov/32471272/

https://www.mdpi.com/1422-0067/21/11/3809

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Targeting Cannabinoid Receptor 2 on Peripheral Leukocytes to Attenuate Inflammatory Mechanisms Implicated in HIV-Associated Neurocognitive Disorder.

 SpringerLink“HIV infection affects an estimated 38 million people. Approximately 50% of HIV patients exhibit neurocognitive dysfunction termed HIV-Associated Neurocognitive Disorder (HAND). HAND is a consequence of chronic low-level neuroinflammation due to HIV entry into the brain. Initially, monocytes become activated in circulation and traffic to the brain. Monocytes, when activated, become susceptible to infection by HIV and can then carry the virus across the blood brain barrier. Once in the brain, activated monocytes secrete chemokines, which recruit virus-specific CD8+ T cells into the brain to further promote neuroinflammation. HAND is closely linked to systemic inflammation driven, in part, by HIV but is also due to persistent translocation of microorganisms across the GI tract. Persistent anti-viral responses in the GI tract compromise microbial barrier integrity. Indeed, HIV patients can exhibit remarkably high levels of activated (CD16+) monocytes in circulation.

Recent studies, including our own, show that HIV patients using medical marijuana exhibit lower levels of circulating CD16+ monocytes than non-cannabis using HIV patients. Cannabis is a known immune modulator, including anti-inflammatory properties, mediated, in part, by ∆9-tetrahydrocannabinol (THC), as well as less characterized minor cannabinoids, such as cannabidiol (CBD), terpenes and presumably other cannabis constituents. The immune modulating activity of THC is largely mediated through cannabinoid receptors (CB) 1 and 2, with CB1 also responsible for the psychotropic properties of cannabis.

Here we discuss the anti-inflammatory properties of cannabinoids in the context of HIV and propose CB2 as a putative therapeutic target for the treatment of neuroinflammation. Graphical Abstract HIV-associated neurocognitive disorder is a systemic inflammatory disease leading to activation of plasmacytoid dendritic cells, monocytes and T cells. Monocyte and CD8 T cell migration across the BBB and interaction with astrocytes promotes neurotoxic inflammatory mediators release. CB2 ligands are proposed as therapeutics capable of suppressing systemic and localized inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/32409991

https://link.springer.com/article/10.1007%2Fs11481-020-09918-7

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Beneficial effects of the phytocannabinoid Δ9-THCV in L-DOPA-induced dyskinesia in Parkinson’s disease.

Neurobiology of Disease“The antioxidant and CB2 receptor agonist properties of Δ9-tetrahydrocannabivarin (Δ9-THCV) afforded neuroprotection in experimental Parkinson’s disease (PD), whereas its CB1 receptor antagonist profile at doses lower than 5 mg/kg caused anti-hypokinetic effects.

In the present study, we investigated the anti-dyskinetic potential of Δ9-THCV (administered i.p. at 2 mg/kg for two weeks), which had not been investigated before.

In summary, our data support the anti-dyskinetic potential of Δ9-THCV, both to delay the occurrence and to attenuate the magnitude of dyskinetic signs. Although further studies are clearly required to determine the clinical significance of these data in humans, the results nevertheless situate Δ9-THCV in a promising position for developing a cannabinoid-based therapy for patients with PD.”

https://www.ncbi.nlm.nih.gov/pubmed/32387338

“Δ9-THCV exhibited anti-dyskinetic properties in L-DOPA-treated Pitx3ak mutant mice. It delayed the onset of dyskinetic signs and reduced their neurochemical changes. It also reduced their intensity when given once dyskinesia was already present. This potential adds to other properties of Δ9-THCV as antiparkinsonian therapy.

In summary, our data support the anti-dyskinetic potential of Δ9-THCV to ameliorate adverse effects caused by L-DOPA, in particular delaying the occurrence and attenuating the magnitude of dyskinetic signs. This adds to its promising symptom-alleviating and neuroprotective properties described previously. Although further studies are clearly required to determine the clinical significance of these data in humans, the results nevertheless situate Δ9-THCV in a promising position for developing a cannabinoid-based therapy for PD patients.”

https://www.sciencedirect.com/science/article/pii/S0969996120301674?via%3Dihub

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Cannabinoid type 2 receptor agonist JWH133 decreases blood pressure of spontaneously hypertensive rats through relieving inflammation in the rostral ventrolateral medulla of the brain.

Journal of Hypertension | The International Society of Hypertension“Neuroinflammation in the rostral ventrolateral medulla (RVLM) has been reported to be associated with hypertension. The upregulation and activation of the cannabinoid type 2 (CB2) receptor may be part of the active process of limiting or downregulating the inflammatory process.

This study was designed to determine the role of the CB2 receptor in blood pressure (BP) through relieving neuroinflammation in the RVLM in spontaneously hypertensive rats (SHRs).

CONCLUSION:

Taken together, our results suggest that exciting the CB2 receptor relieves proinflammatory cytokine levels in the RVLM to decrease the BP, HR and RSNA in SHRs.”

https://www.ncbi.nlm.nih.gov/pubmed/32238784

https://journals.lww.com/jhypertension/Abstract/2020/05000/Cannabinoid_type_2_receptor_agonist_JWH133.15.aspx

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Cannabinoid receptor 2 agonist promotes parameters implicated in mucosal healing in patients with inflammatory bowel disease.

Issues“Cannabis benefits patients with inflammatory bowel disease (IBD).

Cannabinoid receptors are expressed in gut immune cells and in epithelial cells of inflamed guts.

Mucosal healing (MH) requires epithelial layer restoration.

CONCLUSION:

Using ex vivo and in vitro human models, we demonstrated that manipulating the cannabinoid system affects colon cells and secretome characteristics that facilitate MH in IBD.”

https://www.ncbi.nlm.nih.gov/pubmed/32213014

“Experimental studies and recent clinical trials suggest that treatment with cannabis benefits patients with IBD.”

https://journals.sagepub.com/doi/10.1177/2050640619889773

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Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology.

Image result for frontiers in neurology“Microglia, the resident immune cells of the central nervous system, mediate brain homeostasis by controlling neuronal proliferation/differentiation and synaptic activity. In response to external signals from neuropathological conditions, homeostatic (M0) microglia can adopt one of two activation states: the classical (M1) activation state, which secretes mediators of the proinflammatory response, and the alternative (M2) activation state, which presumably mediates the resolution of neuroinflammation and tissue repair/remodeling.

Since chronic inflammatory activation of microglia is correlated with several neurodegenerative diseases, functional modulation of microglial phenotypes has been considered as a potential therapeutic strategy.

The endocannabinoid (eCB) system, composed of cannabinoid receptors and ligands and their metabolic/biosynthetic enzymes, has been shown to activate anti-inflammatory signaling pathways that modulate immune cell functions. Growing evidence has demonstrated that endogenous, synthetic, and plant-derived eCB agonists possess therapeutic effects on several neuropathologies; however, the molecular mechanisms that mediate the anti-inflammatory effects have not yet been identified.

Over the last decade, it has been revealed that the eCB system modulates microglial activation and population. In this review, we thoroughly examine recent studies on microglial phenotype modulation by eCB in neuroinflammatory and neurodegenerative disease conditions.

We hypothesize that cannabinoid 2 receptor (CB2R) signaling shifts the balance of expression between neuroinflammatory (M1-type) genes, neuroprotective (M2-type) genes, and homeostatic (M0-type) genes toward the latter two gene expressions, by which microglia acquire therapeutic functionality.”

https://www.ncbi.nlm.nih.gov/pubmed/32117037

https://www.frontiersin.org/articles/10.3389/fneur.2020.00087/full

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Cannabinoid receptor 2 activation alleviates septic lung injury by promoting autophagy via inhibition of inflammatory mediator release.

Cellular Signalling“Septic lung injury is one of main causes of high mortality in severe patients. Inhibition of excessive inflammatory response is considered as an effective strategy for septic lung injury.

Previous studies have shown that cannabinoid receptor 2 (CB2), a G protein-coupled receptor, play an important role in immunosuppression.

Whether CB2 can be used as a therapeutic target for septic lung injury is unclear. The aim of this study is to explore the role of CB2 in sepsis and its potential mechanism.

These results suggest that CB2 serves as a protective target for septic lung injury by decreasing inflammatory factors, which is associated with the enhancement of autophagy.”

https://www.ncbi.nlm.nih.gov/pubmed/32027949

“Activation of cannabinoid receptor 2 can alleviate sepsis-induced lung injury.”

https://www.sciencedirect.com/science/article/abs/pii/S0898656820300334?via%3Dihub

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Insulinotropic and antidiabetic effects of β-caryophyllene with l-arginine in type 2 diabetic rats.

Journal of Food Biochemistry banner“Beta-caryophyllene (BCP) is a flavoring agent, whereas l-arginine (LA) is used as a food supplement.

They possess insulinotropic and β cell regeneration activities, respectively.

We assessed the antidiabetic potential of BCP, LA, and its combination in RIN-5F cell lines and diabetic rats.

The results indicated that the combination of BCP with LA showed a significant decrease in glucose absorption and an increase in its uptake in tissues and also an increase in insulin secretion in RIN-5F cells. The combination treatment of BCP with LA showed a significant reduction in glucose, lipid levels, and oxidative stress in pancreatic tissue when compared with the diabetic group. Furthermore, the combination of BCP with LA normalized glucose tolerance and pancreatic cell damage in diabetic rats.

In conclusion, the combinational treatment showed significant potentials in the treatment of type 2 diabetes mellitus.

PRACTICAL APPLICATIONS:

Type 2 diabetes mellitus is the most prevalent chronic metabolic disorder affecting a large population.

Beta-caryophyllene is a CB2 receptor agonist shown to have insulinotropic activity.

l-Arginine is a food supplement that possesses beta-cell regeneration property.

The combination of BCP with LA could work as a potential therapeutic intervention, considering the individual pharmacological activities of each.

We evaluated the antidiabetic activity of the combination of BCP with LA in diabetic rats using ex vivo and in vitro experimentations.

Results from the study revealed that the combination of BCP with LA showed a significant (p < .001) reduction in glucose and lipid levels as compared to individual treatment. In vitro study also supports the diabetic potential of the combination of BCP with LA in the glucose-induced insulin secretion in RIN-5F cell lines.

The study indicates a therapeutic approach to treat T2DM by BCP and LA combination as food and dietary supplement.”

https://www.ncbi.nlm.nih.gov/pubmed/31997410

https://onlinelibrary.wiley.com/doi/abs/10.1111/jfbc.13156

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

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Activation of CB2R with AM1241 ameliorates neurodegeneration via the Xist/miR-133b-3p/Pitx3 axis.

Publication cover image“Activation of cannabinoid receptor type II (CB2R) by AM1241 has been demonstrated to protect dopaminergic neurons in Parkinson’s disease (PD) animals.

However, the specific mechanisms of the action of the CB2R agonist AM1241 for PD treatment have not been characterized.

The CB2 receptor agonist AM1241 alleviated PD via regulation of the Xist/miR-133b-3p/Pitx3 axis, and revealed a new approach for PD treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/31989652

https://onlinelibrary.wiley.com/doi/abs/10.1002/jcp.29530

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The Critical Role of Cannabinoid Receptor 2 in URB602-induced Protective Effects Against Renal Ischemia-Reperfusion Injury in the Rat.

 Image result for shock journal“Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and even induces remote organ damage.

Accumulating proofs demonstrates that the endocannabinoid system (ECS) may provide a promising access for treatment strategy of renal IRI associated AKI.

In the current study, using the established renal IRI model of rat, we tested the hypothesis that pretreatment of URB602, 30 min before renal IRI, alleviates kidney injury and relevant distant organ damage via limiting oxidative stress and inflammation.

Taken together, our data indicate that URB602 acts as a reactive oxygen species scavenger and anti-inflammatory media in renal IRI mainly depending on the activation of CB2.”

https://www.ncbi.nlm.nih.gov/pubmed/32004183

 

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