A combination of Δ9-tetrahydrocannabinol and cannabidiol modulates glutamate dynamics in the hippocampus of an animal model of Alzheimer’s disease

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“A combination of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) at non-psychoactive doses was previously demonstrated to reduce cognitive decline in APP/PS1 mice, an animal model of Alzheimer’s disease (AD). However, the neurobiological substrates underlying these therapeutic properties of Δ9-THC and CBD are not fully understood.

Considering that dysregulation of glutamatergic activity contributes to cognitive impairment in AD, the present study evaluates the hypothesis that the combination of these two natural cannabinoids might reverse the alterations in glutamate dynamics within the hippocampus of this animal model of AD.

Interestingly, our findings reveal that chronic treatment with Δ9-THC and CBD, but not with any of them alone, reduces extracellular glutamate levels and the basal excitability of the hippocampus in APP/PS1 mice.

These effects are not related to significant changes in the function and structure of glutamate synapses, as no relevant changes in synaptic plasticity, glutamate signaling or in the levels of key components of these synapses were observed in cannabinoid-treated mice. Our data instead indicate that these cannabinoid effects are associated with the control of glutamate uptake and/or to the regulation of the hippocampal network.

Taken together, these results support the potential therapeutic properties of combining these natural cannabinoids against the excitotoxicity that occurs in AD brains.”

https://pubmed.ncbi.nlm.nih.gov/39232876/

https://www.neurotherapeuticsjournal.org/article/S1878-7479(24)00126-0/fulltext

Pharmacology of Non-Psychoactive Phytocannabinoids and Their Potential for Treatment of Cardiometabolic Disease

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“The use of Cannabis sativa by humans dates back to the third millennium BC, and it has been utilized in many forms for multiple purposes, including production of fibre and rope, as food and medicine, and (perhaps most notably) for its psychoactive properties for recreational use. The discovery of Δ9-tetrahydrocannabinol (Δ9-THC) as the main psychoactive phytocannabinoid contained in cannabis by Gaoni and Mechoulam in 1964 (J Am Chem Soc 86, 1646-1647), was the first major step in cannabis research; since then the identification of the chemicals (phytocannabinoids) present in cannabis, the classification of the pharmacological targets of these compounds and the discovery that the body has its own endocannabinoid system (ECS) have highlighted the potential value of cannabis-derived compounds in the treatment of many diseases, such as neurological disorders and cancers. Although the use of Δ9-THC as a therapeutic agent is constrained by its psychoactive properties, there is growing evidence that non-psychoactive phytocannabinoids, derived from both Cannabis sativa and other plant species, as well as non-cannabinoid compounds found in Cannabis sativa, have real potential as therapeutics. This chapter will focus on the possibilities for using these compounds in the prevention and treatment of cardiovascular disease and related metabolic disturbances.”

https://pubmed.ncbi.nlm.nih.gov/39235486/

https://link.springer.com/chapter/10.1007/164_2024_731

Cannabis sativa L. essential oil: chemical characterisation and antimicrobial activity against methicillin-resistant Staphylococcus pseudintermedius

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“Cannabis sativa L. essential oil has attracted the interest of the scientific community thanks to its numerous biological activities. Several studies have evaluated EOs as alternative therapeutic approaches to limit the use of antibiotics; the present study aimed to evaluate the in vitro inhibitory and bactericidal activity of the essential oils obtained from the leaves and inflorescences of two hemp genotypes against twenty-one multidrug-resistant, methicillin-resistant Staphylococcus pseudintermedius strains isolated from canine clinical samples.

Both EOs were mainly represented by sesquiterpene hydrocarbons, with a prevalence of β-caryophyllene and α-humulene. However, different relative amounts of phytocannabinoids were also detected. Microbiological results evidenced better outcomes for the EO characterised by the highest content of phytocannabinoids, which in turn showed no differences among the tested strains. Nevertheless, both the EOs showed better inhibitory and bactericidal activities than their main constituent, β-caryophyllene, tested individually, highlighting the presence of synergistic effects among the EO compounds.”

https://pubmed.ncbi.nlm.nih.gov/39229937/

https://www.tandfonline.com/doi/full/10.1080/14786419.2024.2398733

The effects of Cannabis sativa and cannabinoids on the inhibition of pancreatic lipase – An enzyme involved in obesity

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“Introduction: Obesity is a chronic noncommunicable disease characterized by excessive body fat that can have negative health consequences. Obesity is a complex disease caused by a combination of genetic, environmental, and lifestyle factors. It is characterized by a discrepancy between caloric intake and expenditure. Obesity increases the risk of acquiring major chronic diseases, including heart disease, stroke, cancer, and Type 2 diabetes mellitus (T2DM). Currently, the inhibition of pancreatic lipases (PL) is a promising pharmacological therapy for obesity and weight management. In this study, the inhibition of pancreatic lipase by Cannabis sativa (C. sativa) plant extract and cannabinoids was investigated.

Methods: The inhibitory effect was assessed using p-nitrophenyl butyrate (pNPB), and the results were obtained by calculating the percentage relative activity and assessed using one-way analysis of variance (ANOVA). Kinetic studies and spectroscopy techniques were used to evaluate the mode of inhibition. Diet-induced; and diabetic rat models were studied to evaluate the direct effects of C. sativa extract on PL activity.

Results: Kinetic analyses showed that the plant extracts inhibited pancreatic lipase, with tetrahydrocannabinol (THC) and cannabinol (CBN) being the potential cause of the inhibition noted for the C. sativa plant extract. CBN and THC inhibited the pancreatic lipase activity in a competitive manner, with the lowest residual enzyme activity of 52 % observed at a 10 μg/mL concentration of CBN and 39 % inhibition at a 25 μg/mL concentration of THC. Circular dichroism (CD) spectroscopy revealed that the inhibitors caused a change in the enzyme’s secondary structure. At low concentrations, THC showed potential for synergistic inhibition with orlistat. C.sativa treatment in an in vivo rat model confirmed its inhibitory effects on pancreatic lipase activity.

Conclusion: The findings in this study provided insight into the use of cannabinoids as pancreatic lipase inhibitors and the possibility of using these compounds to develop new pharmacological treatments for obesity.”

https://pubmed.ncbi.nlm.nih.gov/39232382/

https://www.sciencedirect.com/science/article/pii/S0753332224012423?via%3Dihub

Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models

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“Mutations in mitochondrial energy-producing genes lead to a heterogeneous group of untreatable disorders known as primary mitochondrial diseases (MD). Leigh syndrome (LS) is the most common pediatric MD and is characterized by progressive neuromuscular affectation and premature death.

Here, we show that daily cannabidiol (CBD) administration significantly extends lifespan and ameliorates pathology in two LS mouse models, and improves cellular function in fibroblasts from LS patients. CBD delays motor decline and neurodegenerative signs, improves social deficits and breathing abnormalities, decreases thermally induced seizures, and improves neuropathology in affected brain regions.

Mechanistically, we identify peroxisome proliferator-activated receptor gamma (PPARγ) as a key nuclear receptor mediating CBD’s beneficial effects, while also providing proof of dysregulated PPARγ expression and activity as a common feature in both mouse neurons and fibroblasts from LS patients.

Taken together, our results provide the first evidence for CBD as a potential treatment for LS.”

https://pubmed.ncbi.nlm.nih.gov/39231983/

“Here we report that daily CBD administration significantly extends lifespan and improves clinical signs in mouse models of two distinct LS phenotypic presentations, identifying downstream targets for the beneficial effects of CBD and paving the way for novel therapeutic avenues for LS.”

“CBD prolongs lifespan and improves fitness in Ndufs4-deficient mice”

https://www.nature.com/articles/s41467-024-51884-8


Mechanistic Insights into the Impact of WIN 55, 212-2, a Synthetic Cannabinoid, on Adhesion Molecules PECAM-1 and VE-cadherin in HeLa Cells: Implications on Cancer Processes

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“The endocannabinoid (eCB) system comprises endogenous ligands, cannabinoid receptors (CBRs) and proteins involved in their regulation; its alteration leads to many diseases including cancer. Thus, becomes a therapeutic target for synthetic cannabinoids aimed to control cancer cell proliferation, migration, adhesion and invasion. However, little is known about adhesion molecules regulation through CBRs activation.

Consequently, the aim of this study was to evaluate the effects of a CB1/CB2 agonist, WIN-55, 212-2 (WIN), on the regulation of adhesion molecules PECAM-1 and VE-cadherin in HeLa cells. CBRs expression was evaluated by immunofluorescence staining in HeLa cells. Cell viability by MTT, cell adhesion by crystal violet, adhesion molecules expression and location by Western blot and immunofluorescence staining assays were assessed on cells treated with different WIN concentrations.

Results show that CB1, CB2 and GPR55 receptors are expressed in HeLa cells. Additionally, biphasic effects were observed in their metabolic activity and adhesive properties: low WIN concentrations significantly increased them, in contrast, were decreased at high ones as compared to controls (p < 0.0001), demonstrating that WIN elicits opposite effects depending on the concentration and exposure time. PECAM-1 was detected in cytoplasm, membrane and perinuclear region of HeLa cells, whereas VE-cadherin had a nuclear distribution. There were not significant differences in PECAM-1 and VE-cadherin expression and location, suggesting that WIN does not modulate these proteins.

These findings support the potential use of WIN due to its anticancer properties without dysregulating adhesion molecules. WIN possible contribution to inhibit cancer progression should be further investigated.”

https://pubmed.ncbi.nlm.nih.gov/39228102/

https://www.tandfonline.com/doi/full/10.1080/15376516.2024.2399132

Cannabidiol enhances Atezolizumab efficacy by upregulating PD-L1 expression via the cGAS-STING pathway in triple-negative breast cancer cells

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“The treatment of patients with triple negative breast cancer (TNBC) relies on cytotoxic therapy. Currently, atezolizumab and chemotherapy can be combined in patients with TNBC. However, this approach is not effective for all patients with low reactivity to atezolizumab. As there is a lack of alternative treatment options, new anti-cancer drugs are urgently needed to enhance atezolizumab reactivity against TNBC. Recent strategies have focused on regulating the expression of programmed death-ligand 1 (PD-L1) or enhancing immune response activation by combining anti-cancer drugs with immune checkpoint inhibitors (ICIs).

Cannabidiol (CBD), a cannabinoid component derived from the cannabis plant, has been reported to have anti-cancer therapeutic potential because of its capacity to induce apoptotic cell death in tumor cells while avoiding cytotoxicity in normal cells.

Previous studies have demonstrated the effects of CBD on apoptosis in various cancer cell types. However, the potential role of CBD as an immune modulator in the regulation of PD-L1 expression and anti-cancer immune responses remains to be explored.

In this study, we found that CBD stimulated PD-L1 expression in TNBC cells, which significantly induced the CBD-mediated cGAS-STING pathway activation. Taken together, we demonstrated that the combination of CBD and anti-PD-L1 antibody enhances the anti-cancer immune response in vitro and in vivo experiments.

Our findings identified the mechanism of PD-L1 regulation by CBD in TNBC cells and suggested that CBD could be a potential candidate for the development of new combinatorial strategies with ICIs in TNBC patients.”

https://pubmed.ncbi.nlm.nih.gov/39226389/

https://aacrjournals.org/cancerimmunolres/article/doi/10.1158/2326-6066.CIR-23-0902/747763/Cannabidiol-enhances-Atezolizumab-efficacy-by

Cannabidiol exhibits potent anti-cancer activity against gemcitabine-resistant cholangiocarcinoma via ER-stress induction in vitro and in vivo

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“Background: Failure of treatment with gemcitabine in most cholangiocarcinoma (CCA) patients is due to drug resistance. The therapeutic potential of natural plant secondary compounds with minimal toxicity, such as cannabidiol (CBD), is a promising line of investigation in gemcitabine-resistant CCA. We aim to investigate the effects of CBD on gemcitabine-resistant CCA (KKU-213BGemR) cells in vitro and in vivo.

Materials: In vitro, cell proliferation, colony formation, apoptosis and cell cycle arrest were assessed using MTT assay, clonogenicity assay and flow cytometry. The effect of CBD on ROS production was evaluated using the DCFH-DA fluorescent probe. The mechanism exerted by CBD on ER stress-associated apoptosis was investigated by western blot analysis. A gemcitabine-resistant CCA xenograft model was also used and the expression of PCNA and CHOP were evaluated by immunohistochemical analysis.

Results: The IC50 values of CBD for KKU-213BGemR cells ranged from 19.66 to 21.05 µM. For a non-cancerous immortalized fibroblast cell line, relevant values were 18.29 to 19.21 µM. CBD suppressed colony formation by KKU-213BGemR cells in a dose-dependent manner in the range of 10 to 30 µM. CBD at 30 µM significantly increased apoptosis at early (16.37%) (P = 0.0024) and late (1.8%) stages (P < 0.0001), for a total of 18.17% apoptosis (P = 0.0017), in part by increasing ROS production (P < 0.0001). Multiphase cell cycle arrest significantly increased at G0/G1 with CBD 10 and 20 µM (P = 0.004 and P = 0.017), and at G2/M with CBD 30 µM (P = 0.005). CBD treatment resulted in increased expression of ER stress-associated apoptosis proteins, including p-PERK, BiP, ATF4, CHOP, BAX, and cytochrome c. In xenografted mouse, CBD significantly suppressed tumors at 10 and 40 mg/kg·Bw (P = 0.0007 and P = 0.0278, respectively), which was supported by an increase in CHOP, but a decrease in PCNA expression in tumor tissues (P < 0.0001).

Conclusion: The results suggest that CBD exhibits potent anti-cancer activity against gemcitabine-resistant CCA in vitro and in vivo, in part via ER stress-mediated mechanisms. These results indicate that clinical explorative use of CBD on gemcitabine-resistant CCA patients is warranted.”

https://pubmed.ncbi.nlm.nih.gov/39215312/

“This study suggests that CBD may be a valuable therapeutic option for gemcitabine-resistant CCA, as it inhibits the growth of these resistant cells, induces apoptosis and disrupts the cell cycle. These results are in line with established oncology research and emphasize the potential of CBD as a multifaceted therapeutic agent against gemcitabine resistance in CCA.”

https://bmccomplementmedtherapies.biomedcentral.com/articles/10.1186/s12906-024-04610-2

Anti-inflammatory effects of phytocannabinoids and terpenes on inflamed Tregs and Th17 cells in vitro

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“Aims: Phytocannabinoids and terpenes from Cannabis sativa have demonstrated limited anti-inflammatory and analgesic effects in several inflammatory conditions. In the current study, we test the hypothesis that phytocannabinoids exert immunomodulatory effects in vitro by decreasing inflammatory cytokine expression and activation.

Key methods: CD3/CD28 and lipopolysaccharide activated peripheral blood mononuclear cells (PBMCs) from healthy donors (n = 6) were treated with phytocannabinoid compounds and terpenes in vitro. Flow cytometry was used to determine regulatory T cell (Treg) and T helper 17 (Th17) cell responses to treatments. Cell pellets were harvested for qRT-PCR gene expression analysis of cytokines, cell activation markers, and inflammation-related receptors. Cell culture supernatants were analysed by ELISA to quantify IL-6, TNF-α and IL-10 secretion.

Main findings: In an initial screen of 20 μM cannabinoids and terpenes which were coded to blind investigators, cannabigerol (GL4a), caryophyllene oxide (GL5a) and gamma-terpinene (GL6a) significantly reduced cytotoxicity and gene expression levels of IL6, IL10, TNF, TRPV1, CNR1, HTR1A, FOXP3, RORC and NFKΒ1. Tetrahydrocannabinol (GL7a) suppression of T cell activation was associated with downregulation of RORC and NFKΒ1 gene expression and reduced IL-6 (p < 0.0001) and IL10 (p < 0.01) secretion. Cannabidiol (GL1b) significantly suppressed activation of Tregs (p < 0.05) and Th17 cells (p < 0.05) in a follow-on in vitro dose-response study. IL-6 (p < 0.01) and IL-10 (p < 0.01) secretion was significantly reduced with 50 μM cannabidiol.

Significance: The study provides the first evidence that cannabidiol and tetrahydrocannabinol suppress extracellular expression of both anti- and pro-inflammatory cytokines in an in vitro PBMC model of inflammation.”

https://pubmed.ncbi.nlm.nih.gov/39208564/

https://www.sciencedirect.com/science/article/pii/S0014480024000431?via%3Dihub


Cannabinoids in Integumentary Wound Care: A Systematic Review of Emerging Preclinical and Clinical Evidence

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“This systematic review critically evaluates preclinical and clinical data on the antibacterial and wound healing properties of cannabinoids in integument wounds.

Comprehensive searches were conducted across multiple databases, including CINAHL, Cochrane library, Medline, Embase, PubMed, Web of Science, and LILACS, encompassing records up to May 22, 2024. Eighteen studies met the inclusion criteria. Eleven were animal studies, predominantly utilizing murine models (n = 10) and one equine model, involving 437 animals. The seven human studies ranged from case reports to randomized controlled trials, encompassing 92 participants aged six months to ninety years, with sample sizes varying from 1 to 69 patients. The studies examined the effects of various cannabinoid formulations, including combinations with other plant extracts, crude extracts, and purified and synthetic cannabis-based medications administered topically, intraperitoneally, orally, or sublingually.

Four animal and three human studies reported complete wound closure. Hemp fruit oil extract, cannabidiol (CBD), and GP1a resulted in complete wound closure in twenty-three (range: 5-84) days with a healing rate of 66-86% within ten days in animal studies. One human study documented a wound healing rate of 3.3 cm2 over 30 days, while three studies on chronic, non-healing wounds reported an average healing time of 54 (21-150) days for 17 patients by oral oils with tetrahydrocannabinol (THC) and CBD and topical gels with THC, CBD, and terpenes. CBD and tetrahydrocannabidiol demonstrated significant potential in reducing bacterial loads in murine models. However, further high-quality research is imperative to fully elucidate the therapeutic potential of cannabinoids in the treatment of bacterial skin infections and wounds. Additionally, it is crucial to delineate the impact of medicinal cannabis on the various phases of wound healing.”

https://pubmed.ncbi.nlm.nih.gov/39204426/

“This systematic review methodically evaluates the current evidence on the wound healing and antibacterial properties of medicinal cannabis (MC) in treating integumentary wounds and infections, whether used alone or in combination with other agents. The findings demonstrate that MC possesses significant antibacterial properties and promotes wound healing, showing promising results in both animal models and human studies.”

https://www.mdpi.com/1999-4923/16/8/1081