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

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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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

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

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

Cannabinoids in the descending pain modulatory circuit: Role in inflammation.

Pharmacology & Therapeutics“The legalization of cannabis in some states has intensified interest in the potential for cannabis and its constituents to lead to novel therapeutics for pain.

Our understanding of the cellular mechanisms underlying cannabinoid actions in the brain have lagged behind opioids; however, the current opioid epidemic has also increased attention on the use of cannabinoids as alternatives to opioids for pain, especially chronic pain that requires long-term use.

Endogenous cannabinoids are lipid signaling molecules that have complex roles in modulating neuronal function throughout the brain.

In this review, we discuss cannabinoid functions in the descending pain modulatory pathway, a brain circuit that integrates cognitive and emotional processing of pain to modulate incoming sensory inputs. In addition, we highlight areas where further studies are necessary to understand cannabinoid regulation of descending pain modulation.”

https://www.ncbi.nlm.nih.gov/pubmed/32004514

https://www.sciencedirect.com/science/article/abs/pii/S0163725820300231?via%3Dihub

An evaluation of the anti-hyperalgesic effects of cannabidiolic acid-methyl ester (CBDA-ME) in a preclinical model of peripheral neuropathic pain.

Publication cover image“Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable.

KEY RESULTS:

In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and non-nociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested.

CONCLUSION AND IMPLICATIONS:

Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response.”

https://www.ncbi.nlm.nih.gov/pubmed/31981216

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14997

The Role of Cannabidiol (CBD) in Chronic Pain Management: An Assessment of Current Evidence.

 “Given the growing challenges in chronic pain management coupled with the ongoing consequences of the opioid epidemic, pain management practitioners are looking into more effective, innovative, and safer alternatives to treat pain.

Cannabis-based medicine had been described for hundreds of years but only recently have we seen the more scientific, evidence-based approach to its use, and ongoing investigations continue to explore its potential medical benefits.

While historically more attention has been paid to the psychoactive component of the cannabis plant Δ9-tetrahydrocannabinol (THC), there have been fewer scientific studies on the medical use of the cannabidiol (CBD) – a non-psychoactive component of the cannabis plant.

RECENT FINDINGS:

By examining recent literature, we investigated the use of CBD and its potential role in pain management. Since there are currently no approved pharmaceutical products that contain CBD alone for the management of pain, this review focused on nabiximols (which is a combined product of THC/CBD in a 1:1 ratio) as the only pharmaceutical product available that contains CBD and is being used for the management of pain.

It is difficult to definitely attribute the therapeutic properties to CBD alone since it is always administered with THC.

Based on the available literature, it is difficult to make a recommendation for the use of CBD in chronic pain management. It is also important to note that there are many CBD products currently available as supplements, but these products are non-pharmaceuticals and lack the appropriate clinical studies to support their efficacy claims.”

https://www.ncbi.nlm.nih.gov/pubmed/31980957 

https://link.springer.com/article/10.1007%2Fs11916-020-0835-4

The Endocannabinoid System: A Target for Cancer Treatment.

ijms-logo“In recent years, the endocannabinoid system has received great interest as a potential therapeutic target in numerous pathological conditions.

Cannabinoids have shown an anticancer potential by modulating several pathways involved in cell growth, differentiation, migration, and angiogenesis.

However, the therapeutic efficacy of cannabinoids is limited to the treatment of chemotherapy-induced symptoms or cancer pain, but their use as anticancer drugs in chemotherapeutic protocols requires further investigation.

In this paper, we reviewed the role of cannabinoids in the modulation of signaling mechanisms implicated in tumor progression.”

https://www.ncbi.nlm.nih.gov/pubmed/31979368

https://www.mdpi.com/1422-0067/21/3/747

“In addition to the symptomatic therapy of cancer patients, the antitumor effects of cannabinoids (whether in monotherapy or in combination with other cancer therapies) have promising potential in the treatment of cancer patients.”   https://www.ncbi.nlm.nih.gov/pubmed/31950844
“In addition to the well-known palliative effects of cannabinoids on some cancer-associated symptoms, a large body of evidence shows that these molecules can decrease tumour growth in animal models of cancer. In addition, cannabinoids inhibit angiogenesis and decrease metastasis in various tumour types in laboratory animals. Thus, numerous studies have provided evidence that thc and other cannabinoids exhibit antitumour effects in a wide array of animal models of cancer.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791144/


“Antitumour actions of cannabinoids.”   https://www.ncbi.nlm.nih.gov/pubmed/30019449 

“The endocannabinoid system as a target for the development of new drugs for cancer therapy” https://www.ncbi.nlm.nih.gov/pubmed/12723496

“Cannabinoids as Anticancer Drugs.”  https://www.ncbi.nlm.nih.gov/pubmed/28826542

http://www.thctotalhealthcare.com/category/cancer/

Microglial Phenotypes and Their Relationship to the Cannabinoid System: Therapeutic Implications for Parkinson’s Disease.

 Image result for molecules journal“Parkinson’s disease is a neurodegenerative disorder, the motor symptoms of which are associated classically with Lewy body formation and nigrostriatal degeneration.

Neuroinflammation has been implicated in the progression of this disease, by which microglia become chronically activated in response to α-synuclein pathology and dying neurons, thereby acquiring dishomeostatic phenotypes that are cytotoxic and can cause further neuronal death.

Microglia have a functional endocannabinoid signaling system, expressing the cannabinoid receptors in addition to being capable of synthesizing and degrading endocannabinoids. Alterations in the cannabinoid system-particularly an upregulation in the immunomodulatory CB2 receptor-have been demonstrated to be related to the microglial activation state and hence the microglial phenotype.

This paper will review studies that examine the relationship between the cannabinoid system and microglial activation, and how this association could be manipulated for therapeutic benefit in Parkinson’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31973235

“Microglia activation states and cannabinoid system: Therapeutic implications.  There is accumulating evidence indicating that cannabinoids (CBs) might serve as a promising tool to modify the outcome of inflammation, especially by influencing microglial activity. Microglia has a functional endocannabinoid (eCB) signaling system, composed of cannabinoid receptors and the complete machinery for the synthesis and degradation of eCBs. These actions make CBs a promising therapeutic tool to avoid the detrimental effects of inflammation and possibly paving the way to target microglia in order to generate a reparative milieu in neurodegenerative diseases.” https://www.ncbi.nlm.nih.gov/pubmed/27373505

“These findings imply that a hypofunction or a dysregulation of the endocannabinoid system may be responsible for some of the symptoms of these diseases. Scientific evidence shows that cannabis can provide symptomatic relief in several neurodegenerative diseases.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070159/

“Cannabinoids can have neuroprotective effects, and this can be exploited for therapeutic strategies against neurodegenerative diseases”   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243800/

The anticonvulsant effects of cannabidiol in experimental models of epileptic seizures: from behavior and mechanisms to clinical insights.

Neuroscience & Biobehavioral Reviews“Epilepsy is a neurological disorder characterized by the presence of seizures and neuropsychiatric comorbidities. Despite the number of antiepileptic drugs, one-third of patients did not have their seizures under control, leading to pharmacoresistance epilepsy.

Cannabis sativa has been used since ancient times in Medicine for the treatment of many diseases, including convulsive seizures.

In this context, Cannabidiol (CBD), a non-psychoactive phytocannabinoid present in Cannabis, has been a promising compound for treating epilepsies due to its anticonvulsant properties in animal models and humans, especially in pharmacoresistant patients. In this review, we summarize evidence of the CBD anticonvulsant activities present in a great diversity of animal models. Special attention was given to behavioral CBD effects and its translation to human epilepsies.

CBD anticonvulsant effects are associated with a great variety of mechanisms of action such as endocannabinoid and calcium signaling. CBD has shown effectiveness in the clinical scenario for epilepsies, but its effects on epilepsy-related comorbidities are scarce even in basic research. More detailed and complex behavioral evaluation about CBD effects on seizures and epilepsy-related comorbidities are required.”

https://www.ncbi.nlm.nih.gov/pubmed/31954723

“CBD presents anticonvulsant behavioral effects in animal models of epilepsy. CBD induces neuroprotection in animal models of epileptic seizures. Multiple mechanisms of action are associated to CBD anticonvulsant effects. Animal models support CBD therapeutic use for epilepsies treatment.”

https://www.sciencedirect.com/science/article/pii/S014976341931067X?via%3Dihub

Nose-to-brain Delivery of Natural Compounds for the Treatment of Central Nervous System Disorders.

“Several natural compounds have demonstrated potential for the treatment of central nervous system disorders such as ischemic cerebrovascular disease, glioblastoma, neuropathic pain, neurodegenerative diseases, multiple sclerosis and migraine.

This is due to their well-known antioxidant, anti-inflammatory, neuroprotective, anti-tumor, anti-ischemic and analgesic properties. Nevertheless, many of these molecules have poor aqueous solubility, low bioavailability and extensive gastrointestinal and/or hepatic first-pass metabolism, leading to a quick elimination as well as low serum and tissue concentrations.

Thus, the intranasal route emerged as a viable alternative to oral or parenteral administration, by enabling a direct transport into the brain through the olfactory and trigeminal nerves. With this approach, the blood-brain barrier is circumvented and peripheral exposure is reduced, thereby minimizing possible adverse effects.

OBJECTIVE:

Herein, brain-targeting strategies for the nose-to-brain delivery of natural compounds, including flavonoids, cannabinoids, essential oils and terpenes, will be reviewed and discussed. Brain and plasma pharmacokinetics of these molecules will be analyzed and related to their physicochemical characteristics and formulation properties.

CONCLUSION:

Natural compounds constitute relevant alternatives for the treatment of brain diseases but often require loading into nanocarrier systems to reach the central nervous system in sufficient concentrations. Future challenges lie in a deeper characterization of their therapeutic mechanisms and in the development of effective, safe and brain-targeted delivery systems for their intranasal administration.”

https://www.ncbi.nlm.nih.gov/pubmed/31939728

http://www.eurekaselect.com/178321/article