Tag Archives: cannabinoid receptors

Oral administration of the cannabigerol derivative VCE-003.2 promotes subventricular zone neurogenesis and protects against mutant huntingtin-induced neurodegeneration.

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 “The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB1receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 and nuclear PPARγ receptors, can also be the target of specific cannabinoids.

METHODS:

We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro.

RESULTS:

Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis.

CONCLUSIONS:

The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration.”

https://www.ncbi.nlm.nih.gov/pubmed/30899454

https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-019-0148-x

GPR55 – a putative “type 3” cannabinoid receptor in inflammation.

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“G protein-coupled receptor 55 (GPR55) shares numerous cannabinoid ligands with CB1 and CB2 receptors despite low homology with those classical cannabinoid receptors. The pharmacology of GPR55 is not yet fully elucidated; however, GPR55 utilizes a different signaling system and downstream cascade associated with the receptor. Therefore, GPR55 has emerged as a putative “type 3″ cannabinoid receptor, establishing a novel class of cannabinoid receptor. Furthermore, the recent evidence of GPR55-CB1 and GPR55-CB2 heteromerization along with its broad distribution from central nervous system to peripheries suggests the importance of GPR55 in various cellular processes and pathologies and as a potential therapeutic target in inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/26669245

https://www.degruyter.com/view/j/jbcpp.2016.27.issue-3/jbcpp-2015-0080/jbcpp-2015-0080.xml

The endocannabinoid system in migraine: from bench to pharmacy and back.

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 Image result for curr opin neurol“Migraine is a common, highly disabling disorder. Its treatment involves acute and preventive therapy. Many of available preventive medications are not well tolerated, which results in poor compliance and limited effectiveness. Cannabinoids have been proposed for the treatment of migraine but their efficacy and tolerability are controversial.

RECENT FINDINGS:

Cannabinoids modulate functions and activity of signaling pathways that have a key role in pain control. Growing preclinical evidence and initial clinical findings suggest that modulation of the endocannabinoid system, via endogenous or exogenous cannabinoids may be relevant for migraine via multiple mechanisms.

SUMMARY:

The endocannabinoid system qualifies as an interesting area of research worth exploration in the quest for therapeutic targets for the treatment of migraine.”

https://www.ncbi.nlm.nih.gov/pubmed/30883435

Role of the endocannabinoid system in neurological disorders.

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International Journal of Developmental Neuroscience

“Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that begins in infancy. Although the etiology and pathogenesis are poorly understood, many studies have shown that ASD is closely related to structural and functional defects in the nervous system, especially synaptic transmission. The endocannabinoid (eCB) system is an important regulatory system of the central nervous system that regulates neurotransmission and synaptic plasticity and plays an important role in emotional and social responses and cognitive function. The relationship between eCB system and ASD has attracted increasing attention from scholars. In this review, we discuss the complex lipid signaling network of the eCB system, intracellular transport pathways, abnormal expression and association with various neurological diseases, and direct and indirect evidence for the link between eCB and ASD. Collectively, the findings to date indicate that the eCB system plays a key role in the pathophysiology of ASD and can provide new insights into potential interventions and rehabilitation strategies for ASD.”

https://www.ncbi.nlm.nih.gov/pubmed/30858029

https://www.sciencedirect.com/science/article/abs/pii/S0736574818302995?via%3Dihub

Cannabimimetic plants: are they new cannabinoidergic modulators?

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“Phytochemicals and secondary metabolites able to interact with the endocannabinoid system (Cannabimimetics) have been recently described in a broad range of plants and fruits. These findings can open new alternative avenues to explore for the development of novel therapeutic compounds. The cannabinoids regulate many physiological and pathological functions in both animals and plants. Cannabis sativa is the main plant that produces phytocannabinoids inside resins capable to defend the plant from the aggression of parasites and herbivores. Animals produce anandamide and 2-arachidonoyl glycerol, which thanks to binding with main receptors such as type-1 cannabinoid receptor (CB1R) and the type-2 cannabinoid receptor (CB2R) are involved in inflammation processes and several brain functions. Endogenous cannabinoids, enzymes for synthesis and degradation of cannabinoids, and CB1R and CB2R constitute the endocannabinoid system (ECS). Other plants can produce cannabinoid-like molecules such as perrottetinene extracted from Radula perrottetii, or anandamide and 2-arachidonoyl glycerol extracted from some bryophytes. Moreover, several other secondary metabolites can also interact with the ECS of animals and take the name of cannabimimetics. These phytoextracts not derived from Cannabis sativa can act as receptor agonists or antagonist, or enzyme inhibitors of ECS and can be involved in the inflammation, oxidative stress, cancer, and neuroprotection. Finally, given the evolutionary heterogeneity of the cannabimimetic plants, some authors speculated on the fascinating thesis of the evolutionary convergence between plants and animals regarding biological functions of ECS. The review aims to provide a critical and complete assessment of the botanical, chemical and therapeutic aspects of cannabimimetic plants to evaluate their spread in the world and medicinal potentiality.”

https://www.ncbi.nlm.nih.gov/pubmed/30877436

https://link.springer.com/article/10.1007%2Fs00425-019-03138-x

Analyzing the role of cannabinoids as modulators of Wnt/β-catenin signaling pathway for their use in the management of neuropathic pain.

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Bioorganic & Medicinal Chemistry Letters

“Neuropathic pain is a debilitating form of treatment-resistant chronic pain caused by damage to the nervous system. Cannabinoids have been known for suppressing neuropathic pain by modulating the endo cannabinoid system. Since the canonical Wnt/β-catenin signaling has recently been implicated in pain sensation, we investigated the impact of major cannabinoids (1-6) from the leaves of Cannabis sativa and an epoxy derivative of compound 2, here upon referred to as 2a, on modulating Wnt/β-catenin signaling pathway. The results presented in this study show that compound 1, 2 and 2a exhibited potent inhibitory activity against Wnt/β-catenin pathway in a dose-dependent manner. Compound 2a was seen to inhibit this pathway at slightly lower concentrations than its parent molecule 2, under similar conditions. Taken together, compound 1, 2 and 2a, by virtue of their inhibition of Wnt/β-catenin signaling pathway, could be developed as effective neuroprotective agents for the management of neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/30871771

https://www.sciencedirect.com/science/article/pii/S0960894X19301428?via%3Dihub

β-Caryophyllene, a Natural Sesquiterpene, Attenuates Neuropathic Pain and Depressive-Like Behavior in Experimental Diabetic Mice.

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 View details for Journal of Medicinal Food cover image“Neuropathic pain (NP) is associated with chronic hyperglycemia and emotional disorders such as depression in diabetic patients, complicating the course of treatment. Drugs currently used to treat NP have undesirable side effects, so research on other natural sources has been required.

β-caryophyllene (BCP), a natural sesquiterpene found in some food condiments and considered an agonist to cannabinoid receptor type 2, could have potential therapeutic effects to treat conditions such as NP and emotional disorders. For this reason, we assessed whether BCP modulates nociception, anxiety, and depressive-like behavior in streptozotocin (STZ)-induced experimental diabetic BALB/c female mice.

BCP was orally chronic administrated (10 mg/kg/60 μL). Pain developed with STZ was evaluated with von Frey filament test, SMALGO®, and hot plate test. Anxiety and depression-like behavior were assessed by marbles test, forced swim test, and tail suspension test. BCP significantly reduced glycemia in experimental diabetic mice. The pain was also mitigated by BCP administration. Depression-like behavior assessed with tail suspension test was attenuated with orally chronic BCP administration. Substance P and cytokines such as interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) were also attenuated with BCP administration. NP was positively correlated with substance P and IL-6 and IL-1β release.

Our data using an orally chronic BCP administration in the STZ challenged mice to suggest that glycemia, diabetes-related NP, and depressive-like behavior could be prevented/reduced by dietary BCP.”

https://www.ncbi.nlm.nih.gov/pubmed/30864870

https://www.liebertpub.com/doi/10.1089/jmf.2018.0157

“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

Perspectives on the Role of Endocannabinoids in Autism Spectrum Disorders.

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“Autism spectrum disorders (ASDs) are diagnosed on the basis of three behavioral features, namely, (1) deficits in social communication, (2) absence or delay in language and (3) stereotypy. The consensus regarding the neurological pathogenesis of ASDs is aberrant synaptogenesis and synapse function. Further, it is now widely accepted that ASD is neurodevelopmental in nature, placing emphasis on derangements occurring at the level of intra- and intercellular signaling during corticogenesis. At present, there is an ever-growing list of mutations in putative susceptibility genes in affected individuals, preventing effective transformation of knowledge gathered from basic science research to the clinic. In response, the focus of ASD biology has shifted toward the identification of cellular signaling pathways that are common to various ASD-related mutations in hopes that these shared pathways may serve as more promising treatment targets than targeting individual genes or proteins. To this end, the endogenous cannabinoid (endocannabinoid, eCB) system has recently emerged as a promising therapeutic target in the field of ASD research. The eCB system is altered in several neurological disorders, but the role of these bioactive lipids in ASD etiology remains poorly understood. In this perspective, we review current evidence linking eCB signaling to ASDs and put forth the notion that continued focus on eCBs in autism research may provide valuable insight into pathophysiology and treatment strategies. In addition to its role in modulating transmitter release at mature synapses, the eCB signaling system plays important roles in many aspects of cortical development, and disruption of these effects of eCBs may also be related to ASD pathophysiology.”

https://www.ncbi.nlm.nih.gov/pubmed/30854511

“Advances in our understanding of eCB actions will undoubtedly facilitate pharmacological interventions and further, provide patients the best quality of life possible.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407886/

Members of the endocannabinoid system are distinctly regulated in inflammatory bowel disease and colorectal cancer.

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Scientific Reports

“Preclinical studies have demonstrated that the endocannabinoid system (ECS) plays an important role in the protection against intestinal inflammation and colorectal cancer (CRC); however, human data are scarce. We determined members of the ECS and related components of the ‘endocannabinoidome’ in patients with inflammatory bowel disease (IBD) and CRC, and compared them to control subjects. Anandamide (AEA) and oleoylethanolamide (OEA) were increased in plasma of ulcerative colitis (UC) and Crohn’s disease (CD) patients while 2-arachidonoylglycerol (2-AG) was elevated in patients with CD, but not UC. 2-AG, but not AEA, PEA and OEA, was elevated in CRC patients. Lysophosphatidylinositol (LPI) 18:0 showed higher levels in patients with IBD than in control subjects whereas LPI 20:4 was elevated in both CRC and IBD. Gene expression in intestinal mucosal biopsies revealed different profiles in CD and UC. CD, but not UC patients, showed increased gene expression for the 2-AG synthesizing enzyme diacylglycerol lipase alpha. Transcripts of CNR1 and GPR119 were predominantly decreased in CD. Our data show altered plasma levels of endocannabinoids and endocannabinoid-like lipids in IBD and CRC and distinct transcript profiles in UC and CD. We also report alterations for less known components in intestinal inflammation, such as GPR119, OEA and LPI.”

 https://www.ncbi.nlm.nih.gov/pubmed/30787385
https://www.nature.com/articles/s41598-019-38865-4

Characterization of Cancer-Induced Nociception in a Murine Model of Breast Carcinoma.

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“Severe and poorly treated pain often accompanies breast cancer. Thus, novel mechanisms involved in breast cancer-induced pain should be investigated. Then, it is necessary to characterize animal models that are reliable with the symptoms and progression of the disease as observed in humans. Explaining cancer-induced nociception in a murine model of breast carcinoma was the aim of this study. 4T1 (104) lineage cells were inoculated in the right fourth mammary fat pad of female BALB/c mice; after this, mechanical and cold allodynia, or mouse grimace scale (MGS) were observed for 30 days. To determine the presence of bone metastasis, we performed the metastatic clonogenic test and measure calcium serum levels. At 20 days after tumor induction, the antinociceptive effect of analgesics used to relieve pain in cancer patients (acetaminophen, naproxen, codeine or morphine) or a cannabinoid agonist (WIN 55,212-2) was tested. Mice inoculated with 4T1 cells developed mechanical and cold allodynia and increased MGS. Bone metastasis was confirmed using the clonogenic assay, and hypercalcemia was observed 20 days after cells inoculation. All analgesic drugs reduced the mechanical and cold allodynia, while the MGS was decreased only by the administration of naproxen, codeine, or morphine. Also, WIN 55,212-2 improved all nociceptive measures. This pain model could be a reliable form to observe the mechanisms of breast cancer-induced pain or to observe the efficacy of novel analgesic compounds.”

https://www.ncbi.nlm.nih.gov/pubmed/30850915

https://link.springer.com/article/10.1007%2Fs10571-019-00666-8