Pharmacognosy and Effects of Cannabinoids in the Vascular System

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“Understanding the pharmacodynamics of cannabinoids is an essential subject due to the recent increasing global acceptance of cannabis and its derivation for recreational and therapeutic purposes. Elucidating the interaction between cannabinoids and the vascular system is critical to exploring cannabinoids as a prospective therapeutic agent for treating vascular-associated clinical conditions.

This review aims to examine the effect of cannabinoids on the vascular system and further discuss the fundamental pharmacological properties and mechanisms of action of cannabinoids in the vascular system. Data from literature revealed a substantial interaction between endocannabinoids, phytocannabinoids, and synthetic cannabinoids within the vasculature of both humans and animal models. However, the mechanisms and the ensuing functional response is blood vessels and species-dependent. The current understanding of classical cannabinoid receptor subtypes and the recently discovered atypical cannabinoid receptors and the development of new synthetic analogs have further enhanced the pharmacological characterization of the vascular cannabinoid receptors.

Compelling evidence also suggest that cannabinoids represent a formidable therapeutic candidate for vascular-associated conditions.

Nonetheless, explanations of the mechanisms underlining these processes are complex and paradoxical based on the heterogeneity of receptors and signaling pathways. Further insight from studies that uncover the mechanisms underlining the therapeutic effect of cannabinoids in the treatment of vascular-associated conditions is required to determine whether the known benefits of cannabinoids thus currently outweigh the known/unknown risks.”

https://pubmed.ncbi.nlm.nih.gov/36407955/

https://pubs.acs.org/doi/10.1021/acsptsci.2c00141

Protective effect and mechanism of cannabidiol on myocardial injury in exhaustive exercise training mice

Chemico-Biological Interactions

“Cannabinoid diphenol (CBD) is a non-toxic main component extracted from cannabis, which has the effects of anti-inflammatory, anti-apoptosis and anti-oxidative stress.

In recent years, exercise-induced myocardial injury has become a research hotspot in the field of sports medicine and sports physiology. Exercise-induced myocardial injury is closely related to oxidative stress, inflammatory response and apoptosis. However, there is no clear evidence of the relationship between CBD and exercise-induced myocardial injury.

In this study, by establishing an animal model of exhaustive exercise training in mice, the protective effect of CBD on myocardial injury in mice was elaborated, and the possible molecular mechanism was discussed.

After CBD intervention, the arrangement and rupture of myocardial fiber tissue and the degree of inflammatory cell infiltration were reduced, the deposition of collagen fibers in myocardial tissue decreased. CBD can also significantly inhibit cardiac hypertrophy. Meanwhile, the expression of IL-6, IL-10, TNF-α, Bax, Caspase-3, Bcl-2, MDA-5, IRE-1α, NOX-2, SOD-1, Keap1, Nrf2, HO-1, NF-κB and COX-2 was recovered to normal.

In addition, after CBD intervention, the protein expression of Keap1 was down-regulated, the translocation of Nrf2 from the cytoplasm to the nucleus was significantly increased, then the transcriptional activity was increased, and the expression of the downstream HO-1 antioxidant protein was increased, indicating that CBD may improve the cardiac function of exhaustive exercise training mice by activating Keap1/Nrf2/HO-1 signaling pathway. Molecular docking results also confirmed that CBD had a good binding effect with Keap1/Nrf2/HO-1 signaling pathway proteins.

In conclusion, the protective mechanism of CBD on myocardial injury in exhaustive exercise training mice may be to activate Keap1/Nrf2/HO-1 signaling pathway, and then exert anti-inflammatory, anti-apoptosis and inhibition of oxidative stress.”

https://pubmed.ncbi.nlm.nih.gov/35926578/

https://www.sciencedirect.com/science/article/abs/pii/S0009279722002848?via%3Dihub

Anti-inflammatory effects of cannabidiol against lipopolysaccharides in cardiac sodium channels

“Background: Sepsis, caused by a dysregulated host response to infections, can lead to cardiac arrhythmias. However, the mechanisms underlying sepsis-induced inflammation, and how inflammation provokes cardiac arrhythmias, are not well understood. We hypothesized that CBD may ameliorate lipopolysaccharides (LPS)-induced cardiotoxicity via Toll-like receptor 4 (TLR-4) and cardiac sodium channels (Nav1.5).

Methods and results: We incubated human immune cells (THP-1 macrophages) with LPS for 24 hours, then extracted the THP-1 incubation media. ELISA assay showed that LPS (1 or 5 μg/ml), in a concentration-dependent manner, or MPLA (TLR-4 agonist, 5 μg/ml) stimulated the THP-1 cells to release inflammatory cytokines (TNF-α and IL-6). Prior incubation (4 hours) with cannabidiol (CBD: 5 μM) or C34 (TLR-4 antagonist: 5 μg/ml) inhibited LPS and MPLA-induced release of both IL-6 and TNF-α. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) were subsequently incubated for 24 hours in the media extracted from THP-1 cells incubated with LPS, MPLA alone, or in combination with CBD or C34. Voltage-clamp experiments showed a right shift in the voltage dependence of Nav1.5 activation, steady state fast inactivation (SSFI), increased persistent current and prolonged in silico action potential duration in hiSPC-CM incubated in the LPS or MPLA-THP-1 media. Co-incubation with CBD or C34 rescued the biophysical dysfunction caused by LPS and MPLA.

Conclusion: Our results suggest that CBD may protect against sepsis-induced inflammation and subsequent arrhythmias through (i) inhibition of the release of inflammatory cytokines, antioxidant and anti-apoptotic effects and/or (ii) direct effect on Nav1.5.”

https://pubmed.ncbi.nlm.nih.gov/35906756/

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15936

Vascular responses disrupted by fructose-induced hyperinsulinemia improved with delta-9- tetrahydrocannabinol

“Objectives: In recent years, cannabinoids have been shown to have beneficial effects on diabetic vascular complications.

Vascular complications due to fructose-induced hyperinsulinemia (HI) and diabetic vascular complications have similar mechanisms.

The aim of this experimental study was to observe whether the cannabinoid agonist delta-9-tetrahydrocannabinol (THC) has an ameliorating effect on fructose-induced HI and vascular responses in the aortic ringof rats with HI.

Methods: A total of 24 rats were categorized into 4 groups: control (standard food pellets and water), HI (water containing 10% fructose provided for 12 weeks), THC (1.5 mg/kg/day intraperitoneal administration for 4 weeks), and THC+HI.Body weight was measured again on the last day of the study and the serum insulin level was measured with an enzyme-linked immunosorbent assay. The acetylcholine (ACh) maximum relaxant effect in aortic rings pre-contractedwith noradrenaline (NA) was evaluated.

Results: The body weight of THC and THC+HI groups was lower compared with that of the controls (p<0.01). Increasedinsulin level as a result of fructose consumption decreased with THC administration (p<0.01) while the glucose level increased in all other groups compared with the control group (p<0.01, p<0.05). The NA Emax value decreased in thegroup receiving THC treatment (p<0.01). The increased ACh pD2 value in the HI groups also decreased in the THCtreatment group (p<0.0001). The decreased maximum inhibition value in the HI group increased significantly with THC administration (p<0.001).

Conclusion: THC demonstrated beneficial effects on fructose-induced HI. THC improved ACh-induced endothelialdependent relaxation in HI rat aortic rings.”

http://acikerisim.demiroglu.bilim.edu.tr:8080/xmlui/handle/11446/4516

https://internationalbiochemistry.com/jvi.aspx?un=IJMB-83703&volume=

Inhibition of mitochondrial permeability transition pore and antioxidant effect of Delta-9-tetrahydrocannabinol reduces aluminium phosphide-induced cytotoxicity and dysfunction of cardiac mitochondria

Pesticide Biochemistry and Physiology

“Previous studies have demonstrated that phosphine gas (PH3) released from aluminium phosphide (AlP) can inhibit cytochrome oxidase in cardiac mitochondria and induce generation of free radicals, oxidative stress, alteration in antioxidant defense system and cardiotoxicity.

Available evidence suggests that cannabinoids have protective effects in the reduction of oxidative stress, mitochondrial and cardiovascular damages.

The objective of this study was to evaluate the effect of trans-Δ-9-tetrahydrocannabinol (THC) on AlP-induced toxicity in isolated cardiomyocytes and cardiac mitochondria.

Rat heart isolated cardiomyocytes and mitochondria were cotreated with different concentrations of THC (10, 50 and 100 μM) and IC50 of AlP, then cellular and mitochondrial toxicity parameters were assayed. Treatment with AlP alone increased the cytotoxicity, depletion of cellular glutathione (GSH), mitochondrial reactive oxygen species (ROS) generation, lipid oxidation, mitochondria membrane potential (ΔΨm) collapse and mitochondrial swelling, when compared to control group. However, incubation with THC (10, 50 and 100 μM) attenuated the AlP-induced changes in all these parameters in a THC concentration-dependent manner.

Interestingly, the obtained results showed remarkably significant protective effects of THC by attenuation the different parameters of cytotoxicity, mitochondrial toxicity and oxidative stress induced by ALP in isolated cardiomyocytes and cardiac mitochondria. It is the first report showing the protective effects of THC against AlP-induced toxicity, and these effects are related to antioxidant potential and inhibition of mitochondria permeability transition (MPT) pore.

Based on these results, it was hypothesized that THC may be used as a potential therapeutic agent for the treatment of AlP-induced mitochondrial dysfunction and cardiotoxicity.”

https://pubmed.ncbi.nlm.nih.gov/35715056/

“AIP-induced mitochondrial dysfunction and oxidative stress in mitochondria.•

THC inhibits AIP-induced mitochondrial dysfunction in isolated mitochondria.•

THC reverses AIP-induced mitochondrial swelling in isolated mitochondria.•

THC inhibits AIP-induced MMP (ΔΨm) collapse in isolated mitochondria.•

THC ameliorates AIP-induced cytotoxicity and oxidative stress in cardiomyocytes.”

https://www.sciencedirect.com/science/article/abs/pii/S0048357522000840?via%3Dihub

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Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy

“Diabetic complications, chiefly seen in long-term situations, are persistently deleterious to a large extent, requiring multi-factorial risk reduction strategies beyond glycemic control. Diabetic cardiomyopathy is one of the most common deleterious diabetic complications, being the leading cause of mortality among diabetic patients. The mechanisms of diabetic cardiomyopathy are multi-factorial, involving increased oxidative stress, accumulation of advanced glycation end products (AGEs), activation of various pro-inflammatory and cell death signaling pathways, and changes in the composition of extracellular matrix with enhanced cardiac fibrosis. The novel lipid signaling system, the endocannabinoid system, has been implicated in the pathogenesis of diabetes and its complications through its two main receptors: Cannabinoid receptor type 1 and cannabinoid receptor type 2, alongside other components. However, the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated. This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy. These mechanisms include oxidative/ nitrative stress, inflammation, accumulation of AGEs, cardiac remodeling, and autophagy. A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.”

https://pubmed.ncbi.nlm.nih.gov/35664549/

“Diabetes-induced cardiomyopathy is a deleterious complication of the cardiovascular system characterized by structural and functional changes in the myocardium that ultimately lead to cardiac failure. The mechanisms underlying the development of diabetic cardiomyopathy are complex and involve several pathogenic pathways. A great body of evidence supported a special role of oxidative/nitrative stress and inflammation in the pathogenesis of diabetic cardiomyopathy. The endocannabinoid system has been implicated in the development of several pathological conditions including cardiovascular disorders. Several mechanisms have been proposed as targets by which cannabinoids and the endocannabinoid system could modulate cardiovascular disorders and recent evidence suggested the involvement of this system in the pathogenesis of diabetic cardiomyopathy. Indeed, the manipulation of the endocannabinoid system could represent a promising therapeutic approach for diabetic cardiomyopathy, and several mechanisms have been proposed for this role including its effects on oxidative/nitrative stress, inflammatory pathways, and autophagy together with possible effects on cardiac remodeling. However, more research is needed to define the exact mechanisms of the intervention of the different components of this system in diabetic cardiomyopathy.”

https://www.wjgnet.com/1948-9358/full/v13/i5/387.htm


Cannabidiol Improves Antioxidant Capacity and Reduces Inflammation in the Lungs of Rats with Monocrotaline-Induced Pulmonary Hypertension

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“Cannabidiol (CBD) is a plant-derived compound with antioxidant and anti-inflammatory properties. Pulmonary hypertension (PH) is still an incurable disease. CBD has been suggested to ameliorate monocrotaline (MCT)-induced PH, including reduction in right ventricular systolic pressure (RVSP), a vasorelaxant effect on pulmonary arteries and a decrease in the white blood cell count. The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg daily for 21 days) on the parameters of oxidative stress and inflammation in the lungs of rats with MCT-induced PH. In MCT-induced PH, we found a decrease in total antioxidant capacity (TAC) and glutathione level (GSH), an increase in inflammatory parameters, e.g., tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), nuclear factor kappa B (NF-κB), monocyte chemoattractant protein-1 (MCP-1), and cluster of differentiation 68 (CD68), and the overexpression of cannabinoid receptors type 1 and 2 (CB1-Rs, CB2-Rs). Administration of CBD increased TAC and GSH concentrations, glutathione reductase (GSR) activity, and decreased CB1-Rs expression and levels of inflammatory mediators such as TNF-α, IL -1β, NF-κB, MCP-1 and CD68. In conclusion, CBD has antioxidant and anti-inflammatory effects in MCT-induced PH. CBD may act as an adjuvant therapy for PH, but further detailed preclinical and clinical studies are recommended to confirm our promising results.”

https://pubmed.ncbi.nlm.nih.gov/35630804/

https://www.mdpi.com/1420-3049/27/10/3327


Hempseed ( Cannabis sativa) Peptide H3 (IGFLIIWV) Exerts Cholesterol-Lowering Effects in Human Hepatic Cell Line

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“Hempseed (Cannabis sativa) protein is an important source of bioactive peptides. H3 (IGFLIIWV), a transepithelial transported intestinal peptide obtained from the hydrolysis of hempseed protein with pepsin, carries out antioxidant and anti-inflammatory activities in HepG2 cells. In this study, the main aim was to assess its hypocholesterolemic effects at a cellular level and the mechanisms behind this health-promoting activity. The results showed that peptide H3 inhibited the 3-hydroxy-3-methylglutaryl co-enzyme A reductase (HMGCoAR) activity in vitro in a dose-dependent manner with an IC50 value of 59 μM. Furthermore, the activation of the sterol regulatory element binding proteins (SREBP)-2 transcription factor, followed by the increase of low-density lipoprotein (LDL) receptor (LDLR) protein levels, was observed in human hepatic HepG2 cells treated with peptide H3 at 25 µM. Meanwhile, peptide H3 regulated the intracellular HMGCoAR activity through the increase of its phosphorylation by the activation of AMP-activated protein kinase (AMPK)-pathways. Consequently, the augmentation of the LDLR localized on the cellular membranes led to the improved ability of HepG2 cells to uptake extracellular LDL with a positive effect on cholesterol levels. Unlike the complete hempseed hydrolysate (HP), peptide H3 can reduce the proprotein convertase subtilisin/kexin 9 (PCSK9) protein levels and its secretion in the extracellular environment via the decrease of hepatic nuclear factor 1-α (HNF1-α). Considering all these evidences, H3 may represent a new bioactive peptide to be used for the development of dietary supplements and/or peptidomimetics for cardiovascular disease (CVD) prevention.”

https://pubmed.ncbi.nlm.nih.gov/35565772/

https://www.mdpi.com/2072-6643/14/9/1804

Acute Cannabigerol Administration Lowers Blood Pressure in Mice

“Cannabigerol (CBG) is a cannabinoid compound that is synthesized from Cannabis sativa L. and acts as a substrate for both Δ9-tetraydrocannabinol (Δ9-THC) and cannabidiol (CBD) formation. Given that it does not exhibit psychoactive effects, emerging research has focused on CBG as a potential therapeutic for health conditions including algesia, epilepsy, anxiety, and cancer. While CBG can bind to cannabinoid receptors CB1 and CB2, it has also been described as an agonist at α2-adrenoreceptors (A2-AR), which when activated inhibit the release of norepinephrine from α-adrenergic neurons. This raises the concern that CBG could act at A2-AR to reduce norepinephrine release to cardiovascular end organs, such as the heart and kidneys, causing a reduction in blood pressure. Despite this possibility, there are no reports examining cardiovascular effects of CBG. In this study, we tested the hypothesis that acute CBG administration can lower blood pressure. To test this, six male C57BL/6J mice underwent surgery at 8-10 weeks of age to implant a radiotelemetry probe, which allows for continuous measurement of blood pressure, heart rate and locomotor activity in conscious, freely moving mice. Following 10 days of recovery, baseline measurements were obtained and then mice were randomized to receive intraperitoneal injections of CBG (3.3, 5.6, and 10 mg/kg) and vehicle in a crossover design, with at least one-week washout between treatments. Changes in blood pressure, heart rate, and locomotor activity were measured for two hours post-injection. We found that acute CBG significantly lowered blood pressure compared with vehicle (-12±5 mmHg vehicle vs. -28±2 mmHg at 10 mg/kg CBG; p=0.018), with no apparent dose responsiveness at the doses used in this study (-22±2 mmHg at 3.3 mg/kg CBG; -28±4 at 5.6 mg/kg CBG). The greatest blood pressure reduction was seen at 90-minutes post-CBG administration, which is consistent with reports for peak plasma concentrations of this compound in rodents. The blood pressure lowering effects of CBG occurred in the absence of changes in heart rate or locomotor activity. These overall findings suggest acute CBG may lower blood pressure in phenotypically normal young adult male mice, which may provide caution for the potential of hypotension as an adverse effect of CBG administration. Additional studies are needed to determine if the blood pressure lowering effects of CBG are via an A2-AR mechanism.”

https://pubmed.ncbi.nlm.nih.gov/35555999/

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.0R576

Cannabis sativa extracts protect LDL from Cu 2+-mediated oxidation

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“Background: Multiple therapeutic properties have been attributed to Cannabis sativa. However, further research is required to unveil the medicinal potential of Cannabis and the relationship between biological activity and chemical profile.

Objectives: The primary objective of this study was to characterize the chemical profile and antioxidant properties of three varieties of Cannabis sativa available in Uruguay during progressive stages of maturation.

Methods: Fresh samples of female inflorescences from three stable Cannabis sativa phenotypes, collected at different time points during the end of the flowering period were analyzed. Chemical characterization of chloroform extracts was performed by 1H-NMR. The antioxidant properties of the cannabis sativa extracts, and pure cannabinoids, were measured in a Cu2+-induced LDL oxidation assay.

Results: The main cannabinoids in the youngest inflorescences were tetrahydrocannabinolic acid (THC-A, 242 ± 62 mg/g) and tetrahydrocannabinol (THC, 7.3 ± 6.5 mg/g). Cannabinoid levels increased more than twice in two of the mature samples. A third sample showed a lower and constant concentration of THC-A and THC (177 ± 25 and 1 ± 1, respectively). The THC-A/THC rich cannabis extracts increased the latency phase of LDL oxidation by a factor of 1.2-3.5 per μg, and slowed down the propagation phase of lipoperoxidation (IC50 1.7-4.6 μg/mL). Hemp, a cannabidiol (CBD, 198 mg/g) and cannabidiolic acid (CBD-A, 92 mg/g) rich variety, also prevented the formation of conjugated dienes during LDL oxidation. In fact, 1 μg of extract was able to stretch the latency phase 3.7 times and also to significantly reduce the steepness of the propagation phase (IC50 of 8 μg/mL). Synthetic THC lengthened the duration of the lag phase by a factor of 21 per μg, while for the propagation phase showed an IC50 ≤ 1 μg/mL. Conversely, THC-A was unable to improve any parameter. Meanwhile, the presence of 1 μg of pure CBD and CBD-A increased the initial latency phase 4.8 and 9.4 times, respectively, but did not have an effect on the propagation phase.

Conclusion: Cannabis whole extracts acted on both phases of lipid oxidation in copper challenged LDL. Those effects were just partially related with the content of cannabinoids and partially recapitulated by isolated pure cannabinoids. Our results support the potentially beneficial effects of cannabis sativa whole extracts on the initial phase of atherosclerosis.”

https://pubmed.ncbi.nlm.nih.gov/33123676/

“Our findings support the beneficial effects of Cannabis sativa extracts on the initial phase of atherosclerosis. Since isolated cannabinoids were less effective preventing the oxidation of LDL, a synergistic effect between the diverse arrange of phytochemicals present in complex extracts is supported, reinforcing the entourage hypothesis and the use of whole medicinal cannabis extracts for therapeutic purposes.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-020-00042-0