Category Archives: Endocannabinoid System

The oncogenic role of CB2 in the progression of non-small-cell lung cancer.

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Biomedicine & Pharmacotherapy

“Several studies have verified the important role of cannabinoid and cannabinoid receptor agonists in tumor progression. However, little is known about the precise role of CB2 expression level in the progression of non-small-cell lung cancer (NSCLC).

The expression of CB2 in NSCLC tissues and corresponding paracancerous tissues was examined using immunohistochemical staining assay.

CONCLUSION:

Our data suggested that targeting CB2 may inhibit the growth and survival of NSCLC cells, which the Akt/mTOR/P70S6K pathway may be involved in. These results confer the pro-oncogenic role of CB2 in the progression of NSCLC, thus improving our understanding of CB2 in tumor progression.”

https://www.ncbi.nlm.nih.gov/pubmed/31176172

https://www.sciencedirect.com/science/article/pii/S0753332219321341?via%3Dihub

“Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. These results suggest that CB1 and CB2 could be used as novel therapeutic targets against NSCLC.”  https://www.ncbi.nlm.nih.gov/pubmed/21097714

The cannabinoid receptor 2 agonist, β-caryophyllene, improves working memory and reduces circulating levels of specific proinflammatory cytokines in aged male mice.

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Behavioural Brain Research“Age-related cognitive decline has been associated with proinflammatory cytokines, yet the precise relationship between cognitive decline and cytokine load remains to be elucidated. β-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist with established anti-inflammatory effects that is known to improve memory and increase lifespan. It is of interest to explore the potential of BCP to reduce age-related cognitive decline and proinflammatory cytokine load. In this study, we assessed changes in circulating cytokines across the lifespan, memory performance in young and aged mice, and the effects of BCP on memory function and cytokine load. The plasma levels of 12 cytokines were assessed in male Swiss-Webster mice at 3, 12, and 18 months of age using multiplexed flow cytometry. Working memory was compared in 3 and 12 month-old mice using spontaneous alternations. A dose-response function (100-300 mg/kg, subchronic administration) for BCP-induced memory restoration was determined in 3 and 12 month-old mice. Finally, the effects on cytokine levels of the peak memory enhancing dose of BCP was assessed in 18 month-old mice. Circulating levels of several cytokines significantly increased with age. Multilinear regression analysis showed that IL-23 levels were most strongly associated with age. Aged mice showed deficits in working memory and higher levels of IL-23, both of which were reversed by BCP treatment. BCP appears to reverse age-associated impairments in memory and modulates cytokine production. IL-23 may play a significant role in the aging process, and future research should determine whether it has utility as a biomarker for novel anti-aging therapeutics.”

https://www.ncbi.nlm.nih.gov/pubmed/31173795

https://www.sciencedirect.com/science/article/pii/S0166432819304516?via%3Dihub

“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

Novel CB1-ligands maintain homeostasis of the endocannabinoid-system in ω3- and ω6-long chain-PUFA deficiency.

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The Journal of Lipid Research“Mammalian ω3- and ω6-PUFAs are synthesized from essential fatty acids (EFAs) or supplied by the diet. PUFAs are constitutive elements of membrane-architecture and precursors of lipid signaling molecules. EFAs and long chain PUFAs are precursors in the synthesis of endocannabinoid-ligands of the Gi/o-protein coupled cannabinoid receptors 1 and 2 in the endocannabinoid-system, which critically regulates energy homeostasis, as metabolic signaling system in hypothalamic neuronal circuits, and behavioral parameters. We utilized the auxotrophic fatty acid desaturase 2 deficient (fads2-/-) mouse, deficient in long chain PUFA-synthesis, to follow the age dependent dynamics of the PUFA pattern in the CNS-phospholipidome in unbiased dietary studies of three cohorts on sustained long chain PUFA-free, ω6-arachidonic and ω3-docosahexaenoic acid supplemented diets and their impact on the precursor pool of CB1 ligands. We discovered the transformation of eicosa-all cis-5,11,14-trienoic acid, uncommon in mammalian lipidomes, into two novel endocannabinoids, 20:35,11,14-ethanolamide and 2-20:35,11,14-glycerol, acting as ligands of CB1 in HEK293-cells. Labeling experiments excluded a Δ8-desaturase activity and proved the position-specificity of FADS2. The fads2 -/- mutant might serve as an unbiased model in vivo in the development of novel CB1-agonists and antagonists.”

https://www.ncbi.nlm.nih.gov/pubmed/31167809

http://www.jlr.org/content/early/2019/06/05/jlr.M094664

l-α-Lysophosphatidylinositol (LPI) aggravates myocardial ischemia/reperfusion injury via a GPR55/ROCK-dependent pathway.

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Pharmacology Research & Perspectives banner

“The phospholipid l-α-lysophosphatidylinositol (LPI), an endogenous ligand for GPR55, is elevated in patients with acute coronary syndrome, and a GPR55 antagonist cannabidiol (CBD) reduces experimental ischemia/reperfusion (I/R) injury.”

https://www.ncbi.nlm.nih.gov/pubmed/31149342

https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1002/prp2.487

Bipolar disorder and the endocannabinoid system.

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 Image result for acta neuropsychiatrica“Bipolar disorder (BD) is a debilitating, lifelong neuropsychiatric illness characterised by unsteady mood states which vacillate from (hypo)mania to depression. Despite the availability of pharmaceutical agents which can be effective in ameliorating the acute affective symptoms and prevent episodic relapse, BD is inadequately treated in a subset of patients.

The endocannabinoid system (ECS) is known to exert neuromodulatory effects on other neurotransmitter systems critical in governing emotions. Several studies ranging from clinical to molecular, as well as anecdotal evidence, have placed a spotlight on the potential role of the ECS in the pathophysiology of BD. In this perspective, we present advantages and disadvantages of cannabis use in the management of illness course of BD and provide mechanistic insights into how this system might contribute to the pathophysiology of BD.

RESULTS:

We highlight the putative role of selective cannabinoid receptor 2 (CB2) agonists in BD and briefly discuss findings which provide a rationale for targeting the ECS to assuage the symptoms of BD. Further, data encourage basic and clinical studies to determine how cannabis and cannabinoids (CBs) can affect mood and to investigate emerging CB-based options as probable treatment approaches.

CONCLUSION:

The probable role of the ECS has been almost neglected in BD; however, from data available which suggest a role of ECS in mood control, it is justified to support conducting comprehensive studies to determine whether ECS manipulation could positively affect BD. Based on the limited available data, we suggest that activation of CB2 may stabilise mood in this disorder.”

https://www.ncbi.nlm.nih.gov/pubmed/31159897

https://www.cambridge.org/core/journals/acta-neuropsychiatrica/article/bipolar-disorder-and-the-endocannabinoid-system/0C3191AF7BECA6D5A6EBED3C94CAA57B

Should Oncologists Recommend Cannabis?

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“Cannabis is a useful botanical with a wide range of therapeutic potential. Global prohibition over the past century has impeded the ability to study the plant as medicine. However, delta-9-tetrahydrocannabinol (THC) has been developed as a stand-alone pharmaceutical initially approved for the treatment of chemotherapy-related nausea and vomiting in 1986. The indication was expanded in 1992 to include treatment of anorexia in patients with the AIDS wasting syndrome. Hence, if the dominant cannabinoid is available as a schedule III prescription medication, it would seem logical that the parent botanical would likely have similar therapeutic benefits. The system of cannabinoid receptors and endogenous cannabinoids (endocannabinoids) has likely developed to help us modulate our response to noxious stimuli. Phytocannabinoids also complex with these receptors, and the analgesic effects of cannabis are perhaps the best supported by clinical evidence. Cannabis and its constituents have also been reported to be useful in assisting with sleep, mood, and anxiety. Despite significant in vitro and animal model evidence supporting the anti-cancer activity of individual cannabinoids-particularly THC and cannabidiol (CBD)-clinical evidence is absent. A single intervention that can assist with nausea, appetite, pain, mood, and sleep is certainly a valuable addition to the palliative care armamentarium. Although many healthcare providers advise against the inhalation of a botanical as a twenty-first century drug-delivery system, evidence for serious harmful effects of cannabis inhalation is scant and a variety of other methods of ingestion are currently available from dispensaries in locales where patients have access to medicinal cannabis. Oncologists and palliative care providers should recommend this botanical remedy to their patients to gain first-hand evidence of its therapeutic potential despite the paucity of results from randomized placebo-controlled clinical trials to appreciate that it is both safe and effective and really does not require a package insert.”

https://www.ncbi.nlm.nih.gov/pubmed/31161270

https://link.springer.com/article/10.1007%2Fs11864-019-0659-9

Cannabinoid receptors as therapeutic targets for autoimmune diseases: where do we stand?

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Drug Discovery Today

“Described during the late 1980s and 1990s, cannabinoid receptors (CB1R and CB2R) are G-protein-coupled receptors (GPCRs) activated by endogenous ligands and cannabinoid drug compounds, such as Δ9-THC. Whereas CB1R has a role in the regulation of neurotransmission in different brain regions and mainly mediates the psychoactive effects of cannabinoids, CB2R is found predominantly in the cells and tissues of the immune system and mediates anti-inflammatory and immunomodulatory processes. Studies have demonstrated that CB1R and CB2R can affect the activation of T cells, B cells, monocytes, and microglial cells, inhibiting proinflammatory cytokine expression and upregulating proresolution mediators. Thus, in this review, we summarize the mechanisms by which CBRs interact with the autoimmune environment and the potential to suppress the development and activation of autoreactive cells. Finally, we highlight how the modulation of CB1R and CB2R is advantageous in the treatment of autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes mellitus (T1DM) and rheumatoid arthritis (RA).”

https://www.ncbi.nlm.nih.gov/pubmed/31158514

https://www.sciencedirect.com/science/article/pii/S1359644618304847?via%3Dihub

Countering the Modern Metabolic Disease Rampage With Ancestral Endocannabinoid System Alignment.

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“When primitive vertebrates evolved from ancestral members of the animal kingdom and acquired complex locomotive and neurological toolsets, a constant supply of energy became necessary for their continued survival. To help fulfill this need, the endocannabinoid (eCB) system transformed drastically with the addition of the cannabinoid-1 receptor (CB1R) to its gene repertoire. This established an eCB/CB1R signaling mechanism responsible for governing the whole organism’s energy balance, with its activation triggering a shift toward energy intake and storage in the brain and the peripheral organs (i.e., liver and adipose).

Although this function was of primal importance for humans during their pre-historic existence as hunter-gatherers, it became expendable following the successive lifestyle shifts of the Agricultural and Industrial Revolutions. Modernization of the world has further increased food availability and decreased energy expenditure, thus shifting the eCB/CB1R system into a state of hyperactive deregulated signaling that contributes to the 21st century metabolic disease pandemic.

Studies from the literature supporting this perspective come from a variety of disciplines, including biochemistry, human medicine, evolutionary/comparative biology, anthropology, and developmental biology. Consideration of both biological and cultural evolution justifies the design of improved pharmacological treatments for obesity and Type 2 diabetes (T2D) that focus on peripheral CB1R antagonism. Blockade of peripheral CB1Rs, which universally promote energy conservation across the vertebrate lineage, represents an evolutionary medicine strategy for clinical management of present-day metabolic disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31156558

https://www.frontiersin.org/articles/10.3389/fendo.2019.00311/full

A selective CB2 agonist protects against the inflammatory response and joint destruction in collagen-induced arthritis mice.

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Biomedicine & Pharmacotherapy

“Rheumatoid arthritis (RA) is a chronic, inflammatory, synovitis-dominated systemic disease with unknown etiology. RA is characterized by the involvement of multiple affected joints, symmetry, and invasive arthritis of the limbs, which can lead to joint deformity, cartilage destruction, and loss of function. Cannabinoid receptor 2 (CB2) has potent immunomodulatory and anti-inflammatory effects and is predominantly expressed in non-neuronal tissues. In the current study, the role of CB2 in the process of inflammatory bone erosion in RA was examined. The selective agonist or high-affinity ligand of CB2 (4-quinolone-3-carboxamides CB2 agonist, 4Q3C CB2agonist, 4Q3C) significantly reduced the severity of arthritis, decreased histopathological findings, and markedly reduced bone erosion in collagen-induced arthritis (CIA) mice. In addition, 4Q3C prevented an increase in the nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio and inhibited the formation of osteoclasts in CIA mice. Furthermore, the expression of tumor necrosis factor-alpha, interleukin-1β, cyclooxygenase-2, and inducible nitric oxide synthase was lower in 4Q3C-treated CIA mice than in control CIA mice. Micro-computed tomography corroborated the finding that 4Q3C reduced joint destruction. These data clearly indicate that the CB2-selective agonist, 4Q3C, may have anti-inflammatory and anti-osteoclastogenesis effects in RA and may be considered to be a novel treatment for RA.”

https://www.ncbi.nlm.nih.gov/pubmed/31154267

https://www.sciencedirect.com/science/article/pii/S0753332219307528?via%3Dihub

CB2 Cannabinoid receptor agonist ameliorates novel object recognition but not spatial memory in transgenic APP/PS1 mice.

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Neuroscience Letters

“The cannabinoid receptor 2 (CB2R) has been considered as a potential therapeutic target to ameliorate the neuroinflammation and cognitive impairments of Alzheimer’s disease (AD). However, there has been little research on the diverse roles of CB2R in regulating different forms of cognitive abilities and underlying neuroinflammatory mechanisms. Thus, the focus of the present study was to investigate the effects of CB2R activation on cognitive abilities, activation and phenotype conversion of microglia, and dendrite complexity.

Results showed that CB2R activation normalized the cortex-dependent novel object recognition memory deficit in a novel object recognition test (P < 0.05) and CB2R activation was ineffective for hippocampus-dependent spatial cognitive dysfunction in the Morris water maze test (P > 0.05). Moreover, activation of CB2R did not affect the formation of plaque in either the cortex or hippocampus (P > 0.05). Interestingly, in the cortex but not in the hippocampus of APP/PS1 mice, there was decreased immunofluorescence intensity of Iba1, M1 to M2 microglial phenotype conversion, and restored dendritic complexity after a long treatment period of CB2R agonist (All P < 0.05).

Our results demonstrated that CB2R activation exerts a beneficial role in novel object recognition ability concomitant with region-specific regulation in microglia-mediated neuroinflammation and dendritic complexity in AD-model mice.”

https://www.ncbi.nlm.nih.gov/pubmed/31150731

https://www.sciencedirect.com/science/article/pii/S0304394019303581?via%3Dihub