Tag Archives: cannabinoid

Antidepressant active ingredients from herbs and nutraceuticals used in TCM: pharmacological mechanisms and prospects for drug discovery.

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Pharmacological Research“Depression is a widespread psychological disorder that affects up to 20% of the world’s population. Traditional Chinese medicine (TCM), with its unique curative effect in depression treatment, is gaining increasing attention as the discovery of novel antidepressant drug has become the pursuit of pharmaceutical. This article summarizes the work done on the natural products from TCM that have been reported to conceive antidepressant effects in the past two decades, which can be classified according to various mechanisms including increasing synaptic concentrations of monoamines, alleviating the hypothalamic-pituitary-adrenal (HPA) axis dysfunctions, lightening the impairment of neuroplasticity, fighting towards immune and inflammatory dysregulation. The antidepressant active ingredients identified can be generally divided into saponins, flavonoids, alkaloids, polysaccharides and others. Albiflorin, Baicalein, Berberine chloride, beta-Asarone, cannabidiol, Curcumin, Daidzein, Echinocystic acid (EA), Emodin, Ferulic acid, Gastrodin, Genistein, Ginsenoside Rb1, Ginsenoside Rg1, Ginsenoside Rg3, Hederagenin, Hesperidin, Honokiol, Hyperoside, Icariin, Isoliquiritin, Kaempferol, Liquiritin, L-theanine, Magnolol, Paeoniflorin, Piperine, Proanthocyanidin, Puerarin, Quercetin, Resveratrol (trans), Rosmarinic acid, Saikosaponin A, Senegenin, Tetrahydroxystilbene glucoside and Vanillic acid are Specified in this review. Simultaneously, chemical structures of the active ingredients with antidepressant activities are listed and their sources, models, efficacy and mechanisms are described. Chinese compound prescription and extracts that exert antidepressant effects are also introduced, which may serve as a source of inspiration for further development. In the view of present study, the antidepressant effect of certain TCMs are affirmative and encouraging. However, there are a lot of work needs to be done to evaluate the exact therapeutic effects and mechanisms of those active ingredients, specifically, to establish a unified standard for diagnosis and evaluation of curative effect.”

https://www.ncbi.nlm.nih.gov/pubmed/31706012

https://www.sciencedirect.com/science/article/abs/pii/S1043661819322601?via%3Dihub

Relieving tension: effects of cannabinoids on vagal afferent sensitivity.

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Publication cover image“Endocannabinoids are produced within the gastrointestinal (GI) tract and modulate energy homeostasis and food intake, at least in part, via vagally-dependent actions. The recent paper by Christie et al., [Christie, et al. J Physiol, 2019] demonstrate, for the first time, that cannabinoids exert biphasic effects on the mechanosensitivity of tension-sensitive gastric vagal afferents. At higher concentrations, anandamide increased vagal afferent sensitivity in a CB1 and TRPV1 receptor dependent manner. At lower concentrations, however, anandamide decreased afferent mechanosensitivity; while this was also dependent upon CB1 and TRPV1 receptors, it also appeared dependent upon signaling via the potent orexigenic neurohormone, ghrelin. These results provide further evidence to support the remarkable degree of neuroplasticity within vagal afferent signaling, and suggest that untangling the complex interactions of cannabinoid effects on food intake and energy homeostasis will require careful physiological and pharmacological investigations.”

https://www.ncbi.nlm.nih.gov/pubmed/31707736

https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP279173

“A clear understanding of the mechanisms which mediate these events may provide novel therapeutic targets for the treatment of gastrointestinal disorders due to vago-vagal pathway malfunctions.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318799/

Cannabidiol increases the nociceptive threshold in a preclinical model of Parkinson’s disease.

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Neuropharmacology

“Medications that improve pain threshold can be useful in the pharmacotherapy of Parkinson’s disease (PD). Pain is a prevalent PD’s non-motor symptom with a higher prevalence of analgesic drugs prescription for patients. However, specific therapy for PD-related pain are not available.

Since the endocannabinoid system is expressed extensively in different levels of pain pathway, drugs designed to target this system have promising therapeutic potential in the modulation of pain. Thus, we examined the effects of the 6-hydroxydopamine- induced PD on nociceptive responses of mice and the influence of cannabidiol (CBD) on 6-hydroxydopamine-induced nociception.

Further, we investigated the pathway involved in the analgesic effect of the CBD through the co-administration with a fatty acid amide hydrolase (FAAH) inhibitor, increasing the endogenous anandamide levels, and possible targets from anandamide, i.e., the cannabinoid receptors subtype 1 and 2 (CB1 and CB2) and the transient receptor potential vanilloid type 1 (TRPV1).

We report that 6-hydroxydopamine- induced parkinsonism decreases the thermal and mechanical nociceptive threshold, whereas CBD (acute and chronic treatment) reduces this hyperalgesia and allodynia evoked by 6-hydroxydopamine. Moreover, ineffective doses of either FAAH inhibitor or TRPV1 receptor antagonist potentialized the CBD-evoked antinociception while an inverse agonist of the CB1 and CB2 receptor prevented the antinociceptive effect of the CBD.

Altogether, these results indicate that CBD can be a useful drug to prevent the parkinsonism-induced nociceptive threshold reduction. They also suggest that CB1 and TRPV1 receptors are important for CBD-induced analgesia and that CBD could produce these analgesic effects increasing endogenous anandamide levels.”

https://www.ncbi.nlm.nih.gov/pubmed/31706993

“The CBD treatment decreases hyperalgesia and allodynia in experimental parkinsonism.”

https://www.sciencedirect.com/science/article/pii/S0028390819303703?via%3Dihub

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Cannabidiol promotes apoptosis via regulation of XIAP/Smac in gastric cancer.

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Image result for cell death and disease“According to recent studies, Cannabidiol (CBD), one of the main components of Cannabis sativa, has anticancer effects in several cancers. However, the exact mechanism of CBD action is not currently understood.

Here, CBD promoted cell death in gastric cancer.

We suggest that CBD induced apoptosis by suppressing X-linked inhibitor apoptosis (XIAP), a member of the IAP protein family. CBD reduced XIAP protein levels while increasing ubiquitination of XIAP. The expression of Smac, a known inhibitor of XIAP, was found to be elevated during CBD treatment. Moreover, CBD treatment increased the interaction between XIAP and Smac by increasing Smac release from mitochondria to the cytosol. CBD has also been shown to affect mitochondrial dysfunction.

Taken together, these results suggest that CBD may have potential as a new therapeutic target in gastric cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/31699976

“In conclusion, our study showed that CBD induces apoptotic cell death in gastric cancer cells, which is triggered by ER stress generation and subsequent XIAP inhibition by Smac. Taken together, our results suggest the potential of CBD in novel treatments against gastric cancer.”

 https://www.nature.com/articles/s41419-019-2001-7

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Myorelaxant Effect of Transdermal Cannabidiol Application in Patients with TMD: A Randomized, Double-Blind Trial.

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jcm-logo “The healing properties of cannabidiol (CBD) have been known for centuries.

In this study, we aimed to evaluate the efficiency of the myorelaxant effect of CBD after the transdermal application in patients with myofascial pain.

Results: in Group1, the sEMG masseter activity significantly decreased (11% in the right and 12.6% in the left masseter muscles). In Group2, the sEMG masseter activity was recorded as 0.23% in the right and 3.3% in the left masseter muscles. Pain intensity in VAS scale was significantly decreased in Group1: 70.2% compared to Group2: 9.81% reduction. Patients were asked to apply formulation twice a day for a period of 14 days.

Conclusion: The application of CBD formulation over masseter muscle reduced the activity of masseter muscles and improved the condition of masticatory muscles in patients with myofascial pain.”

https://www.ncbi.nlm.nih.gov/pubmed/31698733

https://www.mdpi.com/2077-0383/8/11/1886

Inhibition of tremulous jaw movements in rats by memantine-Δ9 -tetrahydrocannabinol combination: neuroanatomical correlates.

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British Journal of Pharmacology banner“Memantine and marijuana smoking have been previously found to inhibit tremor in parkinsonian patients, however, the observed effects were relatively weak. The tremorolytic efficacy of memantine and cannabinoid co-administration is unstudied.

This work aimed to evaluate antitremor activity of memantine-Δ9 -tetrahydrocannabinol combination; additionally, the involvement of some neuroanatomical structures in the regulation of the combination effect was evaluated.

EXPERIMENTAL APPROACH:

Haloperidol-induced tremulous jaw movements in rats were used as a model of parkinsonian-like tremor. To evaluate the role of central receptor systems in the drug effect, receptor-targeting agents were administered locally into certain brain areas.

KEY RESULTS:

Memantine and Δ9 -tetrahydrocannabinol alone were without effect, however, co-administration of the drugs significantly decreased number of haloperidol-induced jaw movements. The antitremor activity of the combination was antagonized (i) by injections of L-glutamate into the dorsal striatum, entopeduncular nucleus, substantia nigra pars reticulata, globus pallidus, supratrigeminal and trigeminal motor nuclei but not into the subthalamic and cuneiform nuclei; (ii) by injections of CGS 21680 into the ventrolateral striatum; (iii) by injections of bicuculline into the rostral part of the parvicellular reticular nucleus.

CONCLUSION AND IMPLICATIONS:

Memantine and Δ9 -tetrahydrocannabinol supra-additively inhibit haloperidol-induced tremulous jaw movements. Apparently, the co-administration of the drugs might be a new approach to the treatment of tremor. The presented results identify brain areas influencing parkinsonian-like tremor in rats; these data can help advance the development of novel treatments for repetitive involuntary movements.”

https://www.ncbi.nlm.nih.gov/pubmed/31696510

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14914

“Memantine is a prescription drug used to treat moderate to severe confusion (dementia) related to Alzheimer’s disease. Memantine is available under the following different brand names: Namenda XR, and Namenda.”  https://www.rxlist.com/consumer_memantine_namenda/drugs-condition.htm

A new mechanism for Cannabidiol in regulating the one-carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models.

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Publication cover image“EpidiolexTM , a form of highly purified cannabidiol (CBD) derived from Cannabis plants has demonstrated seizure control activity in patients with Dravet syndrome, without a fully-elucidated mechanism of action. We have employed an unbiased approach to investigate this mechanism at a cellular level.

We use a tractable biomedical model organism, Dictyostelium, to identify protein controlling the effect of CBD and characterize this mechanism. We then translate these results to a Dravet Syndrome mouse model and an acute in vitro seizure model.

Key Results CBD activity is partially dependent upon the mitochondrial glycine cleavage system component, GcvH1 in Dictyostelium, orthologous to the human GCSH protein, which is functionally linked to folate one-carbon metabolism (FOCM). Analysis of FOCM components identified a mechanism for CBD in directly inhibiting methionine synthesis.

Analysis of brain tissue from a Dravet syndrome mouse model also showed drastically altered levels of one-carbon components including methionine, and an in vitro rat seizure model showed an elevated level of methionine that is attenuated following CBD treatment. Conclusions and Implications

Our results suggest a novel mechanism for CBD in the regulating methionine levels, and identify altered one-carbon metabolism in Dravet syndrome and seizure activity.”

https://www.ncbi.nlm.nih.gov/pubmed/31693171

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14892

Targeting the cannabinoid receptor CB2 in a mouse model of l-dopa induced dyskinesia.

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Neurobiology of Disease“L-dopa induced dyskinesia (LID) is a debilitating side-effect of the primary treatment used in Parkinson’s disease (PD), l-dopa. Here we investigate the effect of HU-308, a cannabinoid CB2 receptor agonist, on LIDs.

Utilizing a mouse model of PD and LIDs, induced by 6-OHDA and subsequent l-dopa treatment, we show that HU-308 reduced LIDs as effectively as amantadine, the current frontline treatment. Furthermore, treatment with HU-308 plus amantadine resulted in a greater anti-dyskinetic effect than maximally achieved with HU-308 alone, potentially suggesting a synergistic effect of these two treatments. Lastly, we demonstrated that treatment with HU-308 and amantadine either alone, or in combination, decreased striatal neuroinflammation, a mechanism which has been suggested to contribute to LIDs.

Taken together, our results suggest pharmacological treatments with CB2 agonists merit further investigation as therapies for LIDs in PD patients. Furthermore, since CB2 receptors are thought to be primarily expressed on, and signal through, glia, our data provide weight to suggestion that neuroinflammation, or more specifically, altered glial function, plays a role in development of LIDs.”

https://www.ncbi.nlm.nih.gov/pubmed/31669673

“Collectively, our findings suggest CB2 agonists offer a putative target to treat LIDs, with efficacy comparable to the frontline treatment amantadine. Our study suggests that targeting glial function may be an important strategy for developing therapies for treating LIDs, a major unmet need for PD patients.”

https://www.sciencedirect.com/science/article/pii/S0969996119303213?via%3Dihub

Cannabidiol Regulates Gene Expression in Encephalitogenic T cells Using Histone Methylation and noncoding RNA during Experimental Autoimmune Encephalomyelitis.

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 Scientific Reports“Cannabidiol (CBD) has been shown by our laboratory to attenuate experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).

In this study, we used microarray and next generation sequencing (NGS)-based approaches to determine whether CBD would alter genome-wide histone modification and gene expression in MOG sensitized lymphocytes.

In summary, this study demonstrates that CBD suppresses inflammation through multiple mechanisms, from histone methylation to miRNA to lncRNA.”

https://www.ncbi.nlm.nih.gov/pubmed/31673072

“Marijuana (Cannabis sativa) has many biologically active compounds and its medicinal value has been known for centuries. CBD has been shown to have an anti-inflammatory effect in several animal models. In immune system, studies from our lab as well as those from others have shown that both THC and CBD have anti-inflammatory properties. ”

https://www.nature.com/articles/s41598-019-52362-8

Structure of an allosteric modulator bound to the CB1 cannabinoid receptor.

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Image result for nature chemical biology“The CB1 receptor mediates the central nervous system response to cannabinoids, and is a drug target for pain, anxiety and seizures.

CB1 also responds to allosteric modulators, which influence cannabinoid binding and efficacy.

To understand the mechanism of these compounds, we solved the crystal structure of CB1 with the negative allosteric modulator (NAM) ORG27569 and the agonist CP55940.

The structure reveals that the NAM binds to an extrahelical site within the inner leaflet of the membrane, which overlaps with a conserved site of cholesterol interaction in many G protein-coupled receptors (GPCRs).

The ternary structure with ORG27569 and CP55940 captures an intermediate state of the receptor, in which aromatic residues at the base of the agonist-binding pocket adopt an inactive conformation despite the large contraction of the orthosteric pocket.

The structure illustrates a potential strategy for drug modulation of CB1 and other class A GPCRs.”

https://www.ncbi.nlm.nih.gov/pubmed/31659318

https://www.nature.com/articles/s41589-019-0387-2