Tag Archives: endocannabinoid system

WWL70 protects against chronic constriction injury-induced neuropathic pain in mice by cannabinoid receptor-independent mechanisms.

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“Targeting the endocannabinoid system has emerged as an effective strategy for the treatment of inflammatory and neurological diseases.

Unlike the inhibition of the principal 2-arachidonyl glycerol (2-AG) hydrolytic enzyme monoacylglycerol lipase (MAGL), which leads to 2-AG overload and cannabinoid receptor desensitization, selective inhibition of the minor 2-AG hydrolytic enzyme alpha, beta-hydrolase domain 6 (ABHD6) can provide therapeutic benefits without producing cannabimimetic side effects. We have shown that inhibition of ABHD6 significantly reduces neuroinflammation and exerts neuroprotection in animal models of traumatic brain injury and multiple sclerosis. However, the role of ABHD6 inhibition on neuropathic pain has not been explored.

CONCLUSIONS:

This study reveals a novel mechanism for the antinociceptive effect of the 2-AG catabolic enzyme ABHD6 inhibitor WWL70. Understanding the interaction between endocannabinoid and eicosanoid pathways might provide a new avenue for the treatment of inflammatory and neuropathic pain.”

 https://www.ncbi.nlm.nih.gov/pubmed/29310667
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-017-1045-9

Rimonabant Kills Colon Cancer Stem Cells without Inducing Toxicity in Normal Colon Organoids

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“Colorectal cancer (CRC), like other tumor types, is a highly heterogeneous disease. Within the tumor bulk, intra-tumoral heterogeneity is also ascribable to Cancer Stem Cells (CSCs) subpopulation, characterized by high chemoresistance and the unique ability to retain tumorigenic potential, thus associated to tumor recurrence. High dynamic plasticity of CSCs, makes the development of winning therapeutic strategies even more complex to completely eradicate tumor fuel.

Rimonabant, originally synthesized as antagonist/inverse agonist of Cannabinoid Receptor 1, is able to inactivate Wnt signaling, both in vitro and in vivo, in CRC models, through inhibition of p300-histone acetyltransferase activity. Since Wnt/β-Catenin pathway is the main player underlying CSCs dynamic, this finding candidates Rimonabant as potential modulator of cancer stemness, in CRC.

Overall, results from this work provided new insights on anti-tumor efficacy of Rimonabant, strongly suggesting that it could be a novel lead compound for CRC treatment.

 Anti-tumor action of cannabinoids in CRC was strongly supported by several authors.
The Endocannabinoid (EC) system role in the progression of CRC has been analyzed in vivo in the mouse model of azoxymethane-induced colon carcinogenesis, where cannabinoids-mediated reduction of precancerous lesions in the mouse colon was found.
In CRC cells, agonists and antagonists of both cannabinoid receptors, CB1 and CB2, showed anti-tumor action through induction of cell death with different mechanisms ranging from apoptosis to mitotic catastrophe”
https://www.frontiersin.org/articles/10.3389/fphar.2017.00949/full

Oral cannabis extracts as a promising treatment for the core symptoms of autism spectrum disorder: Preliminary experience in Chilean patients

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Cover image volume 384, Issue

“Preclinical studies and several anecdotal case reports suggest a dysfunctional endocannabinoid system implicated in Autism Spectrum Disorder (ASD).

Objective: To report our preliminary findings in patients with ASD treated with oral cannabis extracts.

Most cases improved at least one of the core symptoms of ASD, including social communication, language, or repetitive behaviors. Additionally, sensory difficulties, food acceptance, feeding and sleep disorders, and/or seizures were improved in most cases.

71,5% of patients received balanced CBD:THC extracts; 19,0% high-CBD; and 9,5% high-THC extracts.

Oral cannabis extracts were well tolerated.

Two patients had more agitation and one had more irritability, effects that were solved by changing the strain.

Conclusion: In this small series of ASD patients, oral cannabis extracts were dramatically more effective than conventional medicines. Large randomized controlled trials are needed to establish efficacy and safety of medicinal cannabis in ASD.”

http://www.jns-journal.com/article/S0022-510X(17)33120-9/fulltext

Do Cannabinoids Confer Neuroprotection Against Epilepsy? An Overview.

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“Cannabinoid-based medications provide not only relief for specific symptoms, but also arrest or delay of disease progression in patients with pain, multiple sclerosis, and other conditions. Although they also seem to hold potential as anticonvulsant agents, evidence of their efficacy in epilepsy is supported by several evidences.

The data reviewed herein lend support to the notion that the endocannabinoid signalling system plays a key modulation role in the activities subserved by the hippocampus, which is directly or indirectly affected in epilepsy patients.

The notion is supported by a variety of anatomical, electrophysiological, biochemical and pharmacological findings. These data suggest the need for developing novel treatments using compounds that selectively target individual elements of the endocannabinoid signalling system.” https://www.ncbi.nlm.nih.gov/pubmed/29290836

“The data reviewed herein demonstrate that cannabinoids provide neuroprotection against brain excitability. They seem to induce at least partial restoration of neurotransmitter dysfunction, inducing an anticonvulsant effect that may be the biological substrate of the complex neurochemical effects reported in experimental and clinical studies. A large body of data suggests that cannabinoids can be harnessed as antiepileptic agents. Finally, among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events and it might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy.”
https://benthamopen.com/FULLTEXT/TONEUJ-11-61

Decisive role of P42/44 mitogen-activated protein kinase in Δ9-tetrahydrocannabinol-induced migration of human mesenchymal stem cells.

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Related image “In past years, medical interest in Δ9-tetrahydrocannabinol (THC), the major psychoactive ingredient of the Cannabis plant, has been renewed due to the elucidation of the endocannabinoid system and diverse other receptor targets involved in biological cannabinoid effects.

The present study therefore investigates the impact of THC on the migration of mesenchymal stem cells (MSCs) which are known to be involved in various regenerative processes such as bone healing.

Collectively, this study demonstrates THC to exert a promigratory effect on MSCs via a CB1 receptor-dependent activation of p42/44 MAPK phosphorylation. This pathway may be involved in regenerative effects of THC and could be a target of pharmacological intervention.”   https://www.ncbi.nlm.nih.gov/pubmed/29285308

“Collectively and to the best of our knowledge, this is the first study reporting a promigratory impact of THC on MSCs, which may be an additional mechanism in the complex network of regenerative action of cannabinoids.”   http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=22517&path[]=71182

Enhancing Endocannabinoid Neurotransmission Augments The Efficacy of Extinction Training and Ameliorates Traumatic Stress-Induced Behavioral Alterations in Rats.

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“Exposure to a traumatic event may result in the development of Post-Traumatic Stress Disorder (PTSD).

Endocannabinoids are crucial modulators of the stress response, interfere with excessive retrieval and facilitate the extinction of traumatic memories. Exposure therapy, combined with pharmacotherapy, represents a promising tool for PTSD treatment.

We investigated whether pharmacological manipulations of the endocannabinoid system during extinction learning ameliorates the behavioral changes induced by trauma exposure.

Our findings suggest that drugs potentiating endocannabinoid neurotransmission may represent promising tools when combined to exposure-based psychotherapies in the treatment of PTSD.”

https://www.ncbi.nlm.nih.gov/pubmed/29265107

https://www.nature.com/articles/npp2017305

Discovery of Selective Cannabinoid CB2 Receptor Agonists by High-Throughput Screening.

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“The endocannabinoid system (ECS) plays a diverse role in human physiology ranging from the regulation of mood and appetite to immune modulation and the response to pain.

Drug development that targets the cannabinoid receptors (CB1 and CB2) has been explored; however, success in the clinic has been limited by the psychoactive side effects associated with modulation of the neuronally expressed CB1 that are enriched in the CNS. CB2, however, are expressed in peripheral tissues, primarily in immune cells, and thus development of CB2-selective drugs holds the potential to modulate pain among other indications without eliciting anxiety and other undesirable side effects associated with CB1 activation.

As part of a collaborative effort among industry and academic laboratories, we performed a high-throughput screen designed to discover selective agonists or positive allosteric modulators (PAMs) of CB2. Although no CB2 PAMs were identified, 167 CB2 agonists were discovered here, and further characterization of four select compounds revealed two with high selectivity for CB2 versus CB1.

These results broaden drug discovery efforts aimed at the ECS and may lead to the development of novel therapies for immune modulation and pain management with improved side effect profiles.”

https://www.ncbi.nlm.nih.gov/pubmed/29257918

 

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