Category Archives: Endocannabinoid System

Restoration of osteogenic differentiation by overexpression of cannabinoid receptor 2 in bone marrow mesenchymal stem cells isolated from osteoporotic patients.

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“Cannabinoid receptor 2 (CNR2) has a critical role in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). CNR2 expression was found to be downregulated in osteoporotic patients.

The present study aimed to investigate the functionality of CNR2 in restoring osteogenic differentiation and mineralization of BMSCs isolated from osteoporotic patients.

The results demonstrated that overexpression of CNR2 in osteoporotic BMSCs increased ALP activity, promoted expression of osteogenic genes and enhanced deposition of mineralized extracellular matrix. In addition, phosphorylation of p38 MAPK was found to be increased by overexpression of CNR2.

In conclusion, the present study indicated that restoration of CNR2 recovered the osteogenic differentiation of BMSCs isolated from osteoporotic patients. This finding may provide a novel strategy for a treatment approach for osteoporosis.”

https://www.ncbi.nlm.nih.gov/pubmed/29250156

https://www.spandidos-publications.com/10.3892/etm.2017.5369

From “Azalla” to Anandamide: Distilling the Therapeutic Potential of Cannabinoids

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Biological Psychiatry Home

“Cannabis has held a unique place in the hearts and minds of people since time immemorial: some have exalted its properties and considered it to be sacred; others have reviled it, considering it a root cause of social evil.

The Assyrians, who lived about 3000 years ago, documented the effects of cannabis on clay tablets. They referred to the plant according to its various uses: as “azalla,” when used as a medical agent; as hemp; and as “gan-zi-gun-nu”—“the drug that takes away the mind”   These seemingly contradictory properties—a substance that can be both a therapeutic agent and a corrupting psychoactive drug—have continued to puzzle us over the ensuing centuries.

As early as the 11th century, excessive cannabis use was suggested to be a cause of “moral degeneracy.”  On the other hand, the ostensible therapeutic value of cannabis was documented extensively in the early 19th century by Sir William B. O’Shaughnessy, an Irish physician working in Calcutta, India.

Given the critical role of the endocannabinoid system in modulating anxiety, it is clear that compounds that can modulate this system offer great promise as therapeutic agents for psychiatric disorders. It is therefore not surprising that the concept of medical marijuana is compelling to laypersons, clinicians, and researchers alike.

While there is not yet a robust body of literature supporting any specific psychiatric indication (despite the regulatory approval in some states of medical marijuana for specific psychiatric disorders), active lines of investigation of therapeutic targets within the endocannabinoid system offer hope for better treatment options.

The evidence at present suggests that the question of whether cannabinoids are good or bad is not dichotomous—it is likely both good and bad depending on the context of use, including dose, duration of exposure, and an individual’s genetic vulnerabilities. Therefore, the challenge that remains is to distill the good therapeutic effects of cannabinoids and thus weed out “gan-zi-gun-nu” from “azalla.””

http://www.biologicalpsychiatryjournal.com/article/S0006-3223(17)32207-2/fulltext

 

Neuroprotective Properties of Endocannabinoids N-Arachidonoyl Dopamine and N-Docosahexaenoyl Dopamine Examined in Neuronal Precursors Derived from Human Pluripotent Stem Cells.

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Biochemistry (Moscow)

“Neuroprotective properties of endocannabinoids N-arachidonoyl dopamine (NADA) and N-docosahexaenoyl dopamine (DHDA) were examined in neuronal precursor cells differentiated from human induced pluripotent stem cells and subjected to oxidative stress. Both compounds exerted neuroprotective activity, which was enhanced by elevating the concentration of the endocannabinoids within the 0.1-10 µM range. However, both agents at 10 µM concentration showed a marked toxic effect resulting in death of ~30% of the cells. Finally, antagonists of cannabinoid receptors as well as the receptor of the TRPV1 endovanilloid system did not hamper the neuroprotective effects of these endocannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/29223163

https://link.springer.com/article/10.1134%2FS0006297917110141

Bioactive products from singlet oxygen photooxygenation of cannabinoids.

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European Journal of Medicinal Chemistry

“Photooxygenation of Δ8 tetrahydrocannabinol (Δ8-THC), Δ9 tetrahydrocannabinol (Δ9-THC), Δ9 tetrahydrocannabinolic acid (Δ9-THCA) and some derivatives (acetate, tosylate and methyl ether) yielded 24 oxygenated derivatives, 18 of which were new and 6 were previously reported, including allyl alcohols, ethers, quinones, hydroperoxides, and epoxides.

Testing these compounds for their modulatory effect on cannabinoid receptors CB1 and CB2 led to the identification of 7 and 21 as CB1 partial agonists with Ki values of 0.043 μM and 0.048 μM, respectively and 23 as a cannabinoid with high binding affinity for CB2 with Ki value of 0.0095 μM, but much less affinity towards CB1 (Ki 0.467 μM).

The synthesized compounds showed cytotoxic activity against cancer cell lines (SK-MEL, KB, BT-549, and SK-OV-3) with IC50 values ranging from 4.2 to 8.5 μg/mL.

Several of those compounds showed antimicrobial, antimalarial and antileishmanial activities, with compound 14 being the most potent against various pathogens.”

https://www.ncbi.nlm.nih.gov/pubmed/29232588

http://www.sciencedirect.com/science/article/pii/S0223523417309467?via%3Dihub

The endocannabinoid system in cardiovascular function: novel insights and clinical implications.

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Clinical Autonomic Research

“Cardiovascular disease is now recognized as the number one cause of death in the world, and the size of the population at risk continues to increase rapidly. The dysregulation of the endocannabinoid (eCB) system plays a central role in a wide variety of conditions including cardiovascular disorders. Cannabinoid receptors, their endogenous ligands, as well as enzymes conferring their synthesis and degradation, exhibit overlapping distributions in the cardiovascular system. Furthermore, the pharmacological manipulation of the eCB system has effects on blood pressure, cardiac contractility, and endothelial vasomotor control. Growing evidence from animal studies supports the significance of the eCB system in cardiovascular disorders.

RESULTS:

Drugs targeting CB1R, CB2R, TRPV1 and PPARs are proven effective in animal models mimicking cardiovascular disorders such as hypertension, atherosclerosis and myocardial infarction. Despite the setback of two clinical trials that exhibited unexpected harmful side-effects, preclinical studies are accelerating the development of more selective drugs with promising results devoid of adverse effects.

CONCLUSION:

Over the last years, increasing evidence from basic and clinical research supports the role of the eCB system in cardiovascular function. Whereas new discoveries are paving the way for the identification of novel drugs and therapeutic targets, the close cooperation of researchers, clinicians and pharmaceutical companies is needed to achieve successful outcomes.”

https://www.ncbi.nlm.nih.gov/pubmed/29222605

https://link.springer.com/article/10.1007%2Fs10286-017-0488-5

Novel Peripherally Restricted Cannabinoid 1 Receptor Selective Antagonist TXX-522 with Prominent Weight-Loss Efficacy in Diet Induced Obese Mice.

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“The clinical development of the first generation of globally active cannabinoid 1 receptor (CB1R) antagonists was suspended because of their adverse neuropsychiatric effects. Selective blockade of peripheral CB1Rs has the potential to provide a viable strategy for the treatment of severe obesity while avoiding these central nervous system side effects.

In the current study, a novel compound (TXX-522) was rationally designed based on the parent nucleus of a classical CB1R-selective antagonist/inverse agonist, rimonabant (SR141716A).

TXX-522 showed good binding, CB1R-selectivity (over the CB2R), and functional antagonist activities in a range of in vitro molecular and cellular assays.

In vivo analysis of the steady state distribution of TXX-522 in the rat brain and blood tissues and the assay of its functional effects on CB1R activity collectively showed that TXX-522 showed minimal brain penetration. Moreover, the in vivo pharmacodynamic study further revealed that TXX-522 had good oral bioavailability and a potent anti-obesity effect, and ameliorated insulin resistance in high-fat diet-induced obese mice. No impact on food intake was observed in this model, confirming the limited brain penetration of this compound.

Thus, the current study indicates that TXX-522 is a novel and potent peripherally acting selective CB1R antagonist with the potential to control obesity and related metabolic disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/29051736

https://www.frontiersin.org/articles/10.3389/fphar.2017.00707/full

LH-21 and Abn-CBD improve β-cell function in isolated human and mouse islets through GPR55-dependent and -independent signalling.

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Diabetes, Obesity and Metabolism

“CB1 and GPR55 are GPCRs expressed by islet β-cells. Pharmacological compounds have been used to investigate their function, but off-target effects of ligands have been reported.

This study examined the effects of Abn-CBD (GPR55 agonist) and LH-21 (CB1 antagonist) on human and mouse islet function, and islets from GPR55-/- mice were used to determine signalling via GPR55.

RESULTS:

Abn-CBD potentiated glucose-stimulated insulin secretion and elevated [Ca2+ ]i in human islets and islets from both GPR55+/+ and GPR55-/- mice. LH-21 also increased insulin secretion and [Ca2+ ]i in human islets and GPR55+/+ mouse islets, but concentrations of LH-21 up to 0.1 μM were ineffective in islets from GPR55-/- mice. Neither ligand affected basal insulin secretion or islet cAMP levels. Abn-CBD and LH-21 reduced cytokine-induced apoptosis in human islets and GPR55+/+ mouse islets, and these effects were suppressed following GPR55 deletion. They also increased β-cell proliferation: the effects of Abn-CBD were preserved in islets from GPR55-/- mice, while those of LH-21 were abolished. Abn-CBD and LH-21 increased AKT phosphorylation in mouse and human islets.

CONCLUSIONS:

This study demonstrated that Abn-CBD and LH-21 improve human and mouse islet β-cell function and viability. Use of islets from GPR55-/- mice suggests that designation of Abn-CBD and LH-21 as GPR55 agonist and CB1 antagonist, should be revised.”

https://www.ncbi.nlm.nih.gov/pubmed/29205751

http://onlinelibrary.wiley.com/doi/10.1111/dom.13180/abstract

Binge Alcohol Exposure Transiently Changes the Endocannabinoid System: A Potential Target to Prevent Alcohol-Induced Neurodegeneration.

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“Excessive alcohol consumption leads to neurodegeneration, which contributes to cognitive decline that is associated with alcohol use disorders (AUDs). The endocannabinoid system has been implicated in the development of AUDs, but little is known about how the neurotoxic effects of alcohol impact the endocannabinoid system. Therefore, the current study investigated the effects of neurotoxic, binge-like alcohol exposure on components of the endocannabinoid system and related N-acylethanolamines (NAEs), and then evaluated the efficacy of fatty acid amide hydrolase (FAAH) inhibition on attenuating alcohol-induced neurodegeneration.

Male rats were administered alcohol according to a binge model, which resulted in a transient decrease in [³H]-CP-55,940 binding in the entorhinal cortex and hippocampus following two days, but not four days, of treatment. Furthermore, binge alcohol treatment did not change the tissue content of the three NAEs quantified, including the endocannabinoid and anandamide. In a separate study, the FAAH inhibitor, URB597 was administered to rats during alcohol treatment and neuroprotection was assessed by FluoroJade B (FJB) staining.

The administration of URB597 during binge treatment did not significantly reduce FJB+ cells in the entorhinal cortex or hippocampus, however, a follow up “target engagement” study found that NAE augmentation by URB597 was impaired in alcohol intoxicated rats. Thus, potential alcohol induced alterations in URB597 pharmacodynamics may have contributed to the lack of neuroprotection by FAAH inhibition.”

https://www.ncbi.nlm.nih.gov/pubmed/29186065

http://www.mdpi.com/2076-3425/7/12/158

Selective cannabinoid 2 receptor stimulation reduces tubular epithelial cell damage following renal ischemia-reperfusion injury.

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Journal of Pharmacology and Experimental Therapeutics “Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which is an increasing problem in the clinic and has been associated with increased rates of mortality. Currently, therapies to treat AKI are not available, so identification of new targets which, upon diagnosis of AKI, can be modulated to ameliorate renal damage is essential.

In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295, was designed, synthesized, and tested in vitro and in silico.

These data suggests that selective CB2 receptor activation could be a potential therapeutic target in the treatment for AKI.”

https://www.ncbi.nlm.nih.gov/pubmed/29187590

http://jpet.aspetjournals.org/content/early/2017/11/29/jpet.117.245522

Targeting Cannabinoid Signaling in the Immune System: “High”-ly Exciting Questions, Possibilities, and Challenges.

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“It is well known that certain active ingredients of the plants of Cannabis genus, i.e., the “phytocannabinoids” [pCBs; e.g., (-)-trans-Δ9-tetrahydrocannabinol (THC), (-)-cannabidiol, etc.] can influence a wide array of biological processes, and the human body is able to produce endogenous analogs of these substances [“endocannabinoids” (eCB), e.g., arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol (2-AG), etc.].

These ligands, together with multiple receptors (e.g., CB1 and CB2 cannabinoid receptors, etc.), and a complex enzyme and transporter apparatus involved in the synthesis and degradation of the ligands constitute the endocannabinoid system (ECS), a recently emerging regulator of several physiological processes.

The ECS is widely expressed in the human body, including several members of the innate and adaptive immune system, where eCBs, as well as several pCBs were shown to deeply influence immune functions thereby regulating inflammation, autoimmunity, antitumor, as well as antipathogen immune responses, etc.

Based on this knowledge, many in vitro and in vivo studies aimed at exploiting the putative therapeutic potential of cannabinoid signaling in inflammation-accompanied diseases (e.g., multiple sclerosis) or in organ transplantation, and to dissect the complex immunological effects of medical and “recreational” marijuana consumption.

Thus, the objective of the current article is (i) to summarize the most recent findings of the field; (ii) to highlight the putative therapeutic potential of targeting cannabinoid signaling; (iii) to identify open questions and key challenges; and (iv) to suggest promising future directions for cannabinoid-based drug development.”   https://www.ncbi.nlm.nih.gov/pubmed/29176975

“Although, many open questions await to be answered, pharmacological modulation of the (endo)cannabinoid signaling, and restoration of the homeostatic eCB tone of the tissues augur to be very promising future directions in the management of several pathological inflammation-accompanied diseases.”   https://www.frontiersin.org/articles/10.3389/fimmu.2017.01487/full