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(A) Cell viability in NSC-34 motor neurons exposed to different CBG concentrations. All CBG doses increased cell viability compared to the control (CTR). (B) Cell viability in NSC-34 exposed to the medium of LPS-stimulated macrophages and in cells pre-treated with CBG. The exposure to the cell culture medium of LPS-stimulated macrophages reduced cell viability, but the pre-treatment with CBG partially restored it. The experiments were performed in triplicate. ** p < 0.01 NSC-34 cells treated with the medium of LPS stimulated macrophages vs. NSC-34 cells pre-treated with CBG and then exposed to the medium of LPS stimulated macrophages; **** p < 0.0001 NSC-34 treated with the medium of LPS stimulated macrophages vs. control.
Source publication
Inflammation and oxidative stress play main roles in neurodegeneration. Interestingly, different natural compounds may be able to exert neuroprotective actions against inflammation and oxidative stress, protecting from neuronal cell loss. Among these natural sources, Cannabis sativa represents a reservoir of compounds exerting beneficial properties...
Citations
... Our investigational data shed light on the potential depression-alleviating effects of cannabigerol, which may be linked to its strong interaction with CB2/CNR2 receptors, as supported by our docking and biochemical analysis, as well as various other research studies by Navarro et al., 2018 and 2020 [62][63][64]. Our results showed that imipramine and cannabigerol effectively mitigated oxidative damage in mice subjected to CUMS, echoing findings from earlier research [65][66][67]. Adding to its antioxidant character, cannabigerol has been reported to inhibit biofilm formation and eradicate preformed biofilms in antibiotic-resistant bacteria, such as methicillinresistant strains [67]. Cannabigerol's ability to modulate oxidative stress has broader therapeutic potential, including reducing anxiety and stress in healthy cannabis users without impairing motor or cognitive function [68]. ...
Introduction: Cannabigerol (CBG), being one of the non-psychotropic phyto-cannabinoid, has been labelled and recognized to be antioxidant and neuroprotective; it may conceivably hold depression-relieving activity. Consequently, the objective of the present research procedure was to explore the depression-alleviating competence of cannabigerol in both stressed and unstressed mice using computational/in-silico modelling, followed by in-vivo analysis.
Method: Target genes for Major Depressive Disorder (MDD) were identified using GeneCards and Swiss Target Prediction, with common targets screened via Venny software. STRING database anal-ysis established protein-protein interactions (PPI), identifying CNR2 (CB2 receptor) as a key target. Molecular docking of CBG with CB2 (PDB ID: 8GUR) showed strong binding, prompting in vivo evaluation. ADME profiling via Schrödinger Maestro v10.5 confirmed CBG’s high oral absorption and favorable pharmacokinetics. Male Swiss albino mice underwent chronic unpredictable mild stress (CUMS) for three successive weeks, with CBG (10, 20, 40 mg/kg) and imipramine (15 mg/kg) administered and various behavioral and biochemical parameters being analyzed.
Results: Cannabigerol demonstrated maximum oral absorption in ADME predictions using Schrö-dinger's Maestro (v10.5). Wayne diagram illustrated MDD-related targets, with CB2 (CNR2) rank-ings in top targets, based on SwissADME and Venny software analysis. Docking analysis revealed a high binding affinity (-10.53) for CB2, outperforming cannabidiol (-9.56) and comparable to Δ9-THC (-10.11). During in vivo evaluation, CBG (40 mg/kg) and Imipramine 15mg/kg significantly reduced CUMS-induced exalted plasma corticosterone, nitrite quantities, and monoamine oxidase-A action in the brain of stressed mice. Additionally, both treatments substantially reversed the unpre-dictable chronic stress-induced decline in catalase action, demonstrating CBG’s possible potential in alleviating depression-like symptoms in mice.
Conclusion: Cannabigerol has shown significant depressive alleviating potential in mice exposed to chronic and unpredictable stress regimes, possibly via interaction with cannabinoid receptors as in-dicated by in-silico modelling, which has been validated by our findings of the in-vivo protocol.
Keywords: Depression, antidepressant, unpredictable stress, cannabigerol, docking, network pharmacology.
... While there are numerous studies related to the pharmacological action of CBD, not as much is known about CBG. While limited, in vitro and in vivo studies have shown that CBG has anti-inflammatory and antioxidant effects in neurological disease models [14,15]. Our previous research shows that a low dose of CBG (2.46 mg/kg/day) reduces inflammation and fibrosis in male MASH mice [16]. ...
... Previous research has emphasized the antioxidative effect of drugs like Nobiletin while elucidating the potential therapeutic intervention to heal MASH-associated liver damage [30]. Our findings support the antioxidative effects seen in other studies regarding the therapeutic potential of CBG [14,15]. The cause of oxidative damage in MASH is largely attributed to mitochondrial dysfunction and the disruption of endoplasmic reticulum redox balance resulting from hepatic lipotoxicity [20]. ...
Background and Aims: Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), involves inflammation, fibrosis, steatosis, and oxidative stress. Previous research from our lab shows that cannabigerol (CBG) reduces inflammation and fibrosis in male MASH mice, but its effects in females remain unknown. Given immune cell population changes in MASLD patients, this study examines CBG’s impact on methionine-choline deficient (MCD) diet-induced MASH in female mice. Methods: MCD-fed female mice are supplemented with two different doses for three weeks. Liver fibrosis, steatosis, oxidative stress, ductular reaction, and inflammation are assessed via Sirius Red, Oil Red O, immunohistochemistry, and immunofluorescence staining. Immune cell changes in non-parenchymal cells (NPCs) are analyzed via flow cytometry. Results: CBG treatment improves liver health by reducing leukocyte infiltration. Both CBG doses significantly decrease fibrosis, oxidative stress, ductular proliferation, and inflammation in MCD-fed mice, including monocyte and T lymphocyte reductions. Additionally, CBG downregulates mast cell activation, inhibiting transforming growth factor (TGF)-β1 release, thereby suppressing hepatic stellate cell activation. This reduces collagen deposition, fibrosis, and ductular proliferation. Conclusions: Our findings provide insights for pre-clinical and clinical research, highlighting CBG’s potential therapeutic role and dosage considerations in mitigating liver fibrosis and inflammation in female patients.
... Aljobaily et al. (2022) showed that a low dose of CBG (2.46 mg/kg/day) reduced leukocyte infiltration, particularly of macrophages in the liver of mice with non-alcoholic steatohepatitis, while a high dose (24.6 mg/kg/day) was not effective. Pretreatment with CBG (7.5 µM) reduced levels of the pro-inflammatory cytokines IL-1β, TNF-α and interferon gamma (IFN-γ) in motor neuron-like hybrid cell line (Neural Stem Cells 34 -NSC-34) treated with LPS-stimulated macrophage medium (Gugliandolo et al., 2018) confirming that CBG is able to modulate important inflammatory pathways involved in the pathogenesis of cardiovascular disease (Table 2). Other authors showed that in a mouse model of bowel disease, treatment with CBG (30 mg/kg/day) reduced levels of proinflammatory cytokines: IL-1β and IFN-γ, and increased levels of antiinflammatory interleukin 10 (IL-10) in the colon, suggesting the usefulness of CBG in the treatment of typically inflammatory diseases (Borrelli et al., 2013) (Table 3). ...
Backgrounds
Cannabigerol (CBG) is a non-psychoactive phytocannabinoid with a broad spectrum of biological effects. However, there is still too little research on its safety especially its effects on the cardiovascular system. Due to its agonist effects on alpha-2-adrenergic receptors (α2AR), it is speculated that it may have applications in the pharmacotherapy of metabolic syndrome, particularly hypertension. Thus, the aim of our review was to analyse the therapeutic potential of CBG in cardiovascular diseases.
Methods
The review was based on searches of the PubMed and Web of Science databases. Keywords were used to identify literature containing therapeutic and mechanistic information on CBG and its potential effects on the cardiovascular system.
Results
A review of the literature shows that CBG exhibits hypotensive effects in mice probably through α2AR agonism. Other numerous in vitro and in vivo studies show that CBG has anti-inflammatory, antioxidant effects and also regulates cell apoptosis. Cannabigerol improved tissue sensitivity to insulin, and also showed efficacy in inhibiting platelet aggregation. However, there are reports of adverse effects of high doses of CBG on liver architecture and function, which calls into question its usefulness and safety profile.
Conclusion
Above mentioned beneficial properties of CBG suggest that it may be useful in treating hypertension and metabolic syndrome. However, there is still a lack of studies on the chronic administration of CBG and its effects on cardiovascular parameters in hypertension condition, which may be necessary to determine its safety and the need for future studies on other indications.
... Given that CBG has no psychoactive effects, its therapeutic application in cancer is an interesting proposition [16]. CBG has been studied for its efficacy in neurological disorders, inflammatory diseases, and infections [17,18]. CBG remains relatively understudied despite its unique chemical profile and potential therapeutic applications in cancer. ...
Objectives
To determine growth inhibitory and anti-cancer effects of Cannabigerol (CBG) in human colorectal cancer cells.
Methods
Anti-proliferative effect of CBG was examined using MTT assay and two colorectal cancer cells (SW480 and LoVo cells). Cell death ratio was analyzed using Annexin V/PI staining experiment. Cell cycle distribution was analyzed using flow cytometry. We also performed western blot analysis on apoptotic marker proteins.
Results
CBG showed growth inhibitory effect in colorectal cancer cells using MTT assay. IC50 concentration of CBG was 34.89 μM in SW480 cells and 23.51 μM in LoVo cells. Annexin V/PI staining showed that CBG treatment increased apoptotic cells from 4.8% to 31.7% in SW480 cells and from 7.7% to 33.9% in LoVo cells. Flow cytometry confirmed that CBG increased sub G1 population via G1 arrest in both SW480 and LoVo cells. Western blot analysis showed that CBG increased expression levels of cell death-related proteins such as cleaved PARP-1, cleaved caspase 9, p53, and caspase 3.
Conclusion
CBG treatment shows antiproliferative activity and causes apoptosis of colorectal cancer cells, suggesting that CBG is applicable as a promising anticancer drug.
... 5 For neurological diseases, the cannabigerol obtained from Cannabis sativa has antiinflammatory and anti-oxidant effects on NSC-34 motor neurons as demonstrated by a reduction in the Interleukin 1 Beta (IL-1β), Tumour Necrosis Factor Alpha (TNF-α), Interferon Gamma (IFN-γ), and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) protein levels. 6 Meanwhile, the use of polar extract and chemical ingredients such as astragaloside IV of Astragalus membranaceus root has been reported in cases of cardiovascular diseases. 7 The product is often employed as a tonic herbal drug and exhibited a protective effect on cardiomyocytes exposed to oxidative stress through an increase in the respiratory capacity and mitochondrial Adenosine Triphosphate (ATP) production. ...
Introduction:
Oral cancer is considered the sixth most common form of cancer worldwide. It causes significant morbidity and mortality, especially in low socioeconomic status groups. However, Cancer chemoprevention encompasses the use of specific compounds to suppress the growth of tumours or inhibit carcinogenesis. Natural products have been identified as one of the most significant sources of anti-cancer agents. Meanwhile, several synthetic drugs exhibit potential cytotoxicity and can induce a wide range of degenerative diseases.
Aim of the review:
This review aims to determine the various plants, vegetables, and fruits possessing natural chemotherapeutic agents against oral cancer cells.
Materials and methods:
A comprehensive review of findings reported in articles retrieved from searches of computerised databases, hand searches, and authoritative texts. Inclusion databases include PubMed, Medline, Web of Science, Scopus, and Scientific. Exclusion Computerised databases: Wikipedia or unknown sources.
Results:
Natural products have fewer side effects, high selectivity, low toxicity, and eliminate cancer cells. Thus, the application of natural products as alternative oral and other cancer therapies has recently demonstrated remarkable progress.
Conclusion:
Natural products have been widely used in developing oral anti-cancer drugs. Most of these natural products present bioactive chemical agents and novel mechanisms of action, such as the inhibition of tumour cell growth, the induction of apoptosis, DNA damage, and the inhibition of topoisomerases I and II. In future, the successful integration of natural products in oral cancer chemoprevention field depends on the advancement of molecular targeting, personalised approaches, and the exploration of novel drug delivery systems. Furthermore, integration of preclinical findings in clinical trials will be important for translating research into impactful interventions.
... CBG appears to regulate redox balance through multiple mechanisms. As mentioned earlier, it reduces the activity of iNOS, a major pro-oxidant factor [8,50]. One study identified the antioxidant effect of CBG in countering hydrogen peroxide (H 2 O 2 )-induced oxidative stress in murine RAW264.7 macrophages. ...
... Additionally, CBG activates PPARγ and modulates the expression of SOD-1, an antioxidant enzyme typically suppressed by pro-inflammatory factors. By influencing these pathways, CBG helps maintain a healthy cellular balance between oxidants and antioxidants [50]. CBG inhibits diacylglycerol lipase (DAGL), an enzyme that creates the endocannabinoid 2-AG. ...
Cannabigerol (CBG), a non-psychoactive cannabinoid found in cannabis, has emerged as a promising therapeutic agent with a diverse range of potential applications. Unlike its well-known counterpart tetrahydrocannabinol (THC), CBG does not induce intoxication, making it an attractive option in the clinic. Recent research has shed light on CBG’s intriguing molecular mechanisms, highlighting its potential to modulate multiple physiological processes. This review delves into the current understanding of CBG’s molecular interactions and explores its therapeutic power to alleviate various conditions, including cancer, metabolic, pain, and inflammatory disorders, amongst others. We discuss how CBG interacts with the endocannabinoid system and other key signaling pathways, such as CB1, CB2, TPR channels, and α2-adrenoceptor, potentially influencing inflammation, pain, neurodegeneration, and other ailments. Additionally, we highlight the ongoing research efforts aimed at elucidating the full spectrum of CBG’s therapeutic potential and its safety profile in clinical settings. Through this comprehensive analysis, we aim to provide a deeper understanding of CBG’s role in promoting human health and pave the way for future research endeavors.
... However, a significantly greater interest has been recruited with those cannabinoid treatments active at preserving neuronal integrity then resulting in delayed disease progression [3,7,27,29,43]. Such neuroprotective properties include cannabinoid receptor-independent antioxidant effects, mainly afforded by the non-psychotropic phytocannabinoid cannabidiol (CBD), whose structure allows this compound to act as scavenger of reactive oxygen species [51], as well as it modulates the antioxidant transcription factor Nuclear Factor (Erythroid-derived 2)-related factor 2 (NRF-2) pathway too [40]. Activating the CB 1 receptor was furtherly proposed as a neuroprotective therapy in experimental PD in a few studies [22,62], despite it may aggravate akinetic signs in certain circumstances and produce psychoactive effects (reviewed in Fernández-Ruiz [28], . ...
Background
The cannabigerol derivative VCE-003.2, which has activity at the peroxisome proliferator-activated receptor-γ has afforded neuroprotection in experimental models of Parkinson’s disease (PD) based on mitochondrial dysfunction (6-hydroxydopamine-lesioned mice) and neuroinflammation (LPS-lesioned mice). Now, we aim to explore VCE-003.2 neuroprotective properties in a PD model that also involves protein dysregulation, other key event in PD pathogenesis.
Methods
To this end, an adeno-associated viral vector serotype 9 coding for a mutated form of the α-synuclein gene (AAV9-SynA53T) was unilaterally delivered in the substantia nigra pars compacta (SNpc) of mice. This model leads to motor impairment and progressive loss of tyrosine hydroxylase-labelled neurons in the SNpc.
Results
Oral administration of VCE-003.2 at 20 mg/kg for 14 days improved the performance of mice injected with AAV9-SynA53T in various motor tests, correlating with the preservation of tyrosine hydroxylase-labelled neurons in the SNpc. VCE-003.2 also reduced reactive microgliosis and astrogliosis in the SNpc. Furthermore, we conducted a transcriptomic analysis in the striatum of mice injected with AAV9-SynA53T and treated with either VCE-003.2 or vehicle, as well as control animals. This analysis aimed to identify gene families specifically altered by the pathology and/or VCE-003.2 treatment. Our data revealed pathology-induced changes in genes related to mitochondrial function, lysosomal cell pathways, immune responses, and lipid metabolism. In contrast, VCE-003.2 treatment predominantly affected the immune response through interferon signaling.
Conclusion
Our study broadens the neuroprotective potential of VCE-003.2, previously described against mitochondrial dysfunction, oxidative stress, glial reactivity and neuroinflammation in PD. We now demonstrate its efficacy against another key pathogenic event in PD as α-synuclein dysregulation. Furthermore, our investigation sheds light on the molecular mechanisms underlying VCE-003.2 revealing its role in regulating interferon signaling. These findings, together with a favorable ADMET profile, enhance the preclinical interest of VCE-003.2 towards its future clinical development in PD.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12993-024-00256-9.
... The recent data indicate that the reduction of the PGE2 levels is accompanied by an increase in the collagen production, thus inhibiting the ageing process, which is evident after the use of another phytocannabinoid, cannabidiol [86]. Moreover, in Alzheimer's disease, CBG has been proven to have the ability to reduce the level of AA, which is an important mediator of inflammation in the skin [53,87], especially after the exposure to UVB radiation when the arachidonic acid inflammatory pathway is activated [88]. CBG has also been shown to reduce the IL-1β-induced PGE2 production in gingival fibroblasts [89]. ...
Phospholipids and their metabolites play an important role in maintaining the membrane integrity and the metabolic functions of keratinocytes under physiological conditions and in the regeneration process after exposure to high-energy UVB radiation. Therefore, in the search for compounds with a protective and regenerative effect on keratinocyte phospholipids, the effectiveness of two antioxidant compounds has been tested: a stable derivative of ascorbic acid, 3-O-ethyl ascorbic acid (EAA) and cannabigerol (CBG), both of which are primarily located in the membrane structures of keratinocytes. In addition, this study has demonstrated that EAA and CBG, especially in a two-component combination, enhance the antioxidant properties of keratinocytes and reduce lipid peroxidation assessed at the level of MDA (malondialdehyde)/neuroprostanes. Moreover, by reducing the activity of enzymes that metabolise phospholipids, free PUFAs (polyunsaturated fatty acids) and endocannabinoids (PLA2; phospholipase A2, COX1/2; cyclooxygenases 1/2, LOX-5; lipoxygenase 5, FAAH; fatty acid amide hydrolase, MAGL; monoacylglycerol lipase), antioxidants have been found to regulate the levels of endocannabinoids (AEA; anandamide, 2-AG; 2-arachidonoylglycerol, PEA; palmitoylethanolamide) and eicosanoids (PGD2; prostaglandin D2, PGE2; prostaglandin E2, 15-d-PGJ2; 15-deoxy-Δ12,14-prostaglandin J2, 15-HETE; 15-hydroxyeicosatetraenoic acid), that are enhanced by UVB radiation. The metabolic effect of both groups of PUFA metabolites is mainly related to the activation of G protein-related receptors (CB1/2; cannabinoid receptor 1 and 2, PPARγ; peroxisome proliferator-activated receptor gamma, TRPV1; transient receptor potential cation channel subfamily V member 1), the expression of which is reduced under the influence of EAA, CBG, and especially the two-component combination. It promotes the regeneration of keratinocyte metabolism disrupted by UVB, particularly in relation to redox balance and inflammation.
... Growing evidence supports the idea that CBG displays potential therapeutic effects in different pathological conditions [31,32]. For instance, studies have shown that CBG (or its derivatives) exerts anti-inflammatory and neuroprotective properties both in vitro [33,34] and in vivo [35][36][37][38][39]. CBG operates through a mechanism of action similar to that of CBD, as it binds weakly to CB1 and CB2 receptors [40]. Besides inhibiting CB1R, it also antagonizes the 5-HT1A receptor, activates alpha-2 adrenoceptors, and modulates endocannabinoid signaling [41]. ...
Cannabis sativa L. produces more than 100 specific bioactive compounds, known as cannabinoids. The major non-psychotropic Cannabis constituent is cannabidiol (CBD), which displays beneficial properties in a variety of medical conditions. However, the potential therapeutic role of other minor phytocannabinoids, such as cannabigerol (CBG), and their use in combination with CBD, has remained largely unexplored. In this study, we wanted to assess the in vivo effects of two novel non-psychotropic cannabinoid formulas, both containing relatively high percentages of CBD but differing mainly for CBG content, hereafter called CBG+ and CBG-formulas. We employed different behavioral tests to evaluate the effects of these formulas at three different dosages on mice locomotor activity, anxiety-related behaviors, short-term memory and sociability. We found that these two formulas display unique behavioral profiles: CBG + formula produced an increase in mice locomotor activity and displayed anxiolytic properties, whereas both formulas improved spatial short-term memory and social interactions. The results obtained suggest that different combinations of phytocannabinoids are able to determine different behavioral effects and highlight the importance of studying the effects of less known phytocannabinoids (like CBG), which used in combination with other phytocannabinoids can change the profile of action of other active compounds (such as CBD).
... For example, CBG, a non-psychoactive pCB, has shown protective effects on both RAW 264.7 (macrophages) and NSC-34 (motor neuron) cell lines, suggesting its possible application in the treatment of neurodegeneration, as well as in other pathological conditions, where oxidative stress and neuroinflammation are major factors, such as Huntington disease, Parkinson disease, multiple sclerosis [53]. Indeed, in an experimental model of neuroinflammation, pretreatment with CBG was observed to lower nitrotyrosine, SOD1, and inducible nitric oxide synthases (iNOS) protein levels, while increasing Nrf-2 levels and preventing apoptosis [54], with similar effects also observed in the presence of CBG-CBD co-administration [55]. ...
The relationship between nuclear factor erythroid 2-related factor 2 (Nrf2) and phytocannabinoids/endocannabinoids (pCBs/eCBs) has been investigated in a variety of models of peripheral illnesses, with little clarification on their interaction within the central nervous system (CNS). In this context, evidence suggests that the Nrf2-pCBs/eCBS interaction is relevant in modulating peroxidation processes and the antioxidant system. Nrf2, one of the regulators of cellular redox homeostasis, appears to have a protective role toward damaging insults to neurons and glia by enhancing those genes involved in the regulation of homeostatic processes. Specifically in microglia and macroglia cells, Nrf2 can be activated, and its signaling pathway modulated, by both pCBs and eCBs. However, the precise effects of pCBs and eCBs on the Nrf2 signaling pathway are not completely elucidated yet, making their potential clinical employment still not fully understood.
