Cannabidiol alleviates right ventricular fibrosis by inhibiting the transforming growth factor β pathway in monocrotaline-induced pulmonary hypertension in rats

Posted on by
Reply
pubmed logo

“Cannabidiol (CBD) is a non-intoxicating compound of Cannabis with anti-fibrotic properties. Pulmonary hypertension (PH) is a disease that can lead to right ventricular (RV) failure and premature death.

There is evidence that CBD reduces monocrotaline (MCT)-induced PH, including reducing right ventricular systolic pressure (RVSP), vasorelaxant effect on pulmonary arteries, and decreasing expression of profibrotic markers in the lungs.

The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg daily for 21 days) on profibrotic parameters in the RVs of MCT-induced PH rats.

In MCT-induced PH, we found an increase in profibrotic parameters and parameters related to RV dysfunction, i.e. plasma pro-B-type natriuretic peptide (NT-proBNP), cardiomyocyte width, interstitial and perivascular fibrosis area, amount of fibroblasts and fibronectin, as well as overexpression of the transforming growth of factor β1 (TGF-β1), galectin-3 (Gal-3), suppressor of mothers against decapentaplegic 2 (SMAD2), phosphorylated SMAD2 (pSMAD2) and alpha-smooth muscle actin (α-SMA). In contrast, vascular endothelial cadherin (VE-cadherin) levels were decreased in the RVs of MCT-induced PH rats.

Administration of CBD reduced the amount of plasma NT-proBNP, the width of cardiomyocytes, the amount of fibrosis area, fibronectin and fibroblast expression, as well as decreased the expression of TGF-β1, Gal-3, SMAD2, pSMAD2, and increased the level of VE-cadherin.

Overall, CBD has been found to have the anti-fibrotic potential in MCT-induced PH. As such, CBD may act as an adjuvant therapy for PH, however, further detailed investigations are recommended to confirm our promising results.”

https://pubmed.ncbi.nlm.nih.gov/37187449/

“CBD may be used in the future as add-on therapy in the treatment of PH.”

https://www.sciencedirect.com/science/article/pii/S0925443923001199?via%3Dihub

“CBD has potential to boost heart function in PH patients: Early study”

CBD has potential to boost heart function in PH patients: Early study

Cannabidiol inhibits lung proliferation in monocrotaline-induced pulmonary hypertension in rats

Posted on by
Reply
pubmed logo

“Cannabidiol (CBD) is a safe and well-tolerated plant-derived drug with anti-proliferative properties.

Pulmonary hypertension (PH) is a rapidly progressive and still incurable disease.

CBD diminishes monocrotaline (MCT)-induced PH, including reduced right ventricular systolic pressure, pulmonary vascular hypertrophy, and right ventricular remodeling.

The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg once daily for 21 days) on selected remodeling parameters in the lung of MCT-induced PH rats.

In MCT-induced PH, we found an increase in profibrotic parameters, e.g., transforming growth factor β1 (TGF-β1), galectin-3 (Gal-3), procollagen I, collagen I, C-propeptide, matrix metalloproteinase 9 (MMP-9) and an increased number of mast cells. In our study, we observed that the TGF-β1, Gal-3, procollagen I, collagen I, C-propeptide, and mast cell levels in lung tissue were decreased after CBD administration to MCT-treated rats.

In summary, CBD treatment has an anti-proliferative effect on MCT-induced PH. Given the beneficial multidirectional effects of CBD on PH, we believe that CBD can be used as an adjuvant PH therapy, but this argument needs to be confirmed by clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/36634588/

“CBD may be used in the future as an adjuvant therapy in the treatment of PH.”

https://www.sciencedirect.com/science/article/pii/S0753332223000227?via%3Dihub

Cannabidiol attenuates pulmonary arterial hypertension by improving vascular smooth muscle cells mitochondrial function

Posted on by
Reply
pubmed logo

“Rationale: Pulmonary arterial hypertension (PAH) is a chronic disease associated with enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) and dysfunctional mitochondria, and the clinical therapeutic option for PAH is very limited. Recent studies showed that cannabidiol (CBD), a non-psychoactive constituent of cannabinoids, possessed antioxidant effect towards several cardiovascular diseases, whereas the mechanistic effect of CBD in PAH is unknown. 

Methods: In this study, the effects of CBD in PAH were determined by analyzing its preventive and therapeutic actions in PAH rodent models in vivo and PASMCs’ proliferation test in vitro. Additionally, CBD’s roles in mitochondrial function and oxidant stress were also assessed in PASMCs. 

Results: We found that CBD reversed the pathological changes observed in both Sugen-hypoxia and monocrotaline-induced PAH rodent models in a cannabinoid receptors-independent manner. Our results also demonstrated that CBD significantly inhibited the PASMCs’ proliferation in PAH mice with less inflammation and reactive oxygen species levels. Moreover, CBD alleviated rodent PAH by recovering mitochondrial energy metabolism, normalizing the hypoxia-induced oxidant stress, reducing the lactate overaccumulation and abnormal glycolysis. 

Conclusions: Taken together, these findings confirm an important role for CBD in PAH pathobiology.”

https://pubmed.ncbi.nlm.nih.gov/33859746/

“We demonstrated that CBD inhibited the hyperproliferation of PASMCs, recovered the function of mitochondria, alleviated the oxidant stress in PASMCs and inhibited the excessive glycolysis, accompanied by metabolic improvement (Graphical abstract). Consistently, CBD successfully ameliorated hypoxia-induced PAH in mice and MCT-induced PAH in rats. Taken together, our study strongly suggested that CBD might provide a promising novel potential for the treatment of PAH.”

https://www.thno.org/v11p5267.htm

Exploring the evolutionary trajectory and functional landscape of cannabinoid receptors: A comprehensive bioinformatic analysis

Posted on by
Reply
pubmed logo

“The bioinformatic analysis of cannabinoid receptors (CBRs) CB1 and CB2 reveals a detailed picture of their structure, evolution, and physiological significance within the endocannabinoid system (ECS). The study highlights the evolutionary conservation of these receptors evidenced by sequence alignments across diverse species including humans, amphibians, and fish. Both CBRs share a structural hallmark of seven transmembrane (TM) helices, characteristic of class A G-protein-coupled receptors (GPCRs), which are critical for their signalling functions. The study reports a similarity of 44.58 % between both CBR sequences, which suggests that while their evolutionary paths and physiological roles may differ, there is considerable conservation in their structures. Pathway databases like KEGG, Reactome, and WikiPathways were employed to determine the involvement of the receptors in various signalling pathways. The pathway analyses integrated within this study offer a detailed view of the CBRs interactions within a complex network of cannabinoid-related signalling pathways. High-resolution crystal structures (PDB ID: 5U09 for CB1 and 5ZTY for CB2) provided accurate structural information, showing the binding pocket volume and surface area of the receptors, essential for ligand interaction. The comparison between these receptors’ natural sequences and their engineered pseudo-CBRs (p-CBRs) showed a high degree of sequence identity, confirming the validity of using p-CBRs in receptor-ligand interaction studies. This comprehensive analysis enhances the understanding of the structural and functional dynamics of cannabinoid receptors, highlighting their physiological roles and their potential as therapeutic targets within the ECS.”

https://pubmed.ncbi.nlm.nih.gov/38943725/

https://www.sciencedirect.com/science/article/pii/S1476927124001269?via%3Dihub

Effects of Cannabinoids on Intestinal Motility, Barrier Permeability, and Therapeutic Potential in Gastrointestinal Diseases

Posted on by
Reply
pubmed logo

“Cannabinoids and their receptors play a significant role in the regulation of gastrointestinal (GIT) peristalsis and intestinal barrier permeability. This review critically evaluates current knowledge about the mechanisms of action and biological effects of endocannabinoids and phytocannabinoids on GIT functions and the potential therapeutic applications of these compounds.

The results of ex vivo and in vivo preclinical data indicate that cannabinoids can both inhibit and stimulate gut peristalsis, depending on various factors. Endocannabinoids affect peristalsis in a cannabinoid (CB) receptor-specific manner; however, there is also an important interaction between them and the transient receptor potential cation channel subfamily V member 1 (TRPV1) system.

Phytocannabinoids such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) impact gut motility mainly through the CB1 receptor. They were also found to improve intestinal barrier integrity, mainly through CB1 receptor stimulation but also via protein kinase A (PKA), mitogen-associated protein kinase (MAPK), and adenylyl cyclase signaling pathways, as well as by influencing the expression of tight junction (TJ) proteins.

The anti-inflammatory effects of cannabinoids in GIT disorders are postulated to occur by the lowering of inflammatory factors such as myeloperoxidase (MPO) activity and regulation of cytokine levels. In conclusion, there is a prospect of utilizing cannabinoids as components of therapy for GIT disorders.”

https://pubmed.ncbi.nlm.nih.gov/38928387/

“In summary, our narrative review highlights the complex interaction between cannabinoids and gastrointestinal physiology, shedding light on their potential therapeutic applications in the treatment of GIT diseases.

The findings highlight the diverse effects of cannabinoids on motility, intestinal permeability, and inflammation, which are mediated by interactions with endocannabinoids and cannabinoid receptors. It is noteworthy that cannabinoids such as THC and CBD exhibit receptor-specific effects on GIT motility via CB1 receptors, causing inhibition of muscle contractility, which may suggest targets for therapeutic interventions. Moreover, the involvement of CB1 and CB2 receptors in regulating intestinal permeability underscores the complexity of mechanisms mediated by cannabinoids in gastrointestinal health.

In addition, cannabinoids show promise as anti-inflammatory agents, offering potential benefits in the treatment of Crohn’s disease, ulcerative colitis, and IBD. Moreover, their role in modulating intestinal motility and relieving pain implicates cannabinoids as potential agents for improving quality of life in gastrointestinal disorders, especially chronic such as IBS. The results of clinical trials and data on the adverse effects of phytocannabinoids indicate that further research is needed to elucidate the exact mechanisms and optimize therapeutic strategies to realize the full potential of cannabinoids in clinical practice.”

https://www.mdpi.com/1422-0067/25/12/6682

Combinations of Cannabinoids with Silver Salts or Silver Nanoparticles for Synergistic Antibiotic Effects against Methicillin-Resistant Staphylococcus aureus

Posted on by
Reply
pubmed logo

“Silver has been shown to improve the antibiotic effects of other drugs against both Gram- positive and -negative bacteria. In this study, we investigated the antibiotic potential of cannabidiol (CBD), cannabichromene (CBC) and cannabigerol (CBG) and their acidic counterparts (CBDA, CBCA, CBGA) against Gram-positive bacteria and further explored the additive or synergistic effects of silver nitrate or silver nanoparticles using 96-well plate growth assays and viability (CFUs- colony-forming units).

All six cannabinoids had strong antibiotic effects against MRSA with minimal inhibitory concentrations (MICs) of 2 mg/L for CBG, CBD and CBCA; 4 mg/L for CBGA; and 8 mg/L for CBC and CBDA. Using 96-well checkerboard assays, CBC, CBG and CBGA showed full or partial synergy with silver nitrate; CBC, CBDA and CBGA were fully synergistic with silver nanoparticles against MRSA.

Using CFU assays, combinations of CBC, CBGA and CBG with either silver nitrate or silver nanoparticles, all at half or quarter MICs, demonstrated strong, time-dependent inhibition of bacterial growth (silver nitrate) and bactericidal effects (silver nanoparticles). These data will lead to further investigation into possible biomedical applications of specific cannabinoids in combination with silver salts or nanoparticles against drug-resistant Gram-positive bacteria.”

https://pubmed.ncbi.nlm.nih.gov/38927140/

“In conclusion, these studies confirm the antibiotic activity of CBG, CBC and CBD and the acidic forms of these agents against drug-resistant Gram-positive bacteria. The addition of silver, either as salts or nanoparticles, to select cannabinoids allows for much improved and, in some cases, synergistic antibiotic activity. Collectively, these findings strongly support further investigation of cannabinoid-enhanced silver preparations to assess their antimicrobial spectrum of activity and potential application in wound dressings or catheter coatings for an extended and more powerful antibiotic profile.”

https://www.mdpi.com/2079-6382/13/6/473

Potential of CBD Acting on Cannabinoid Receptors CB1 and CB2 in Ischemic Stroke

Posted on by
Reply
pubmed logo

“Stroke is one of the leading causes of death. It not only affects adult people but also many children. It is estimated that, every year, 15 million people suffer a stroke worldwide. Among them, 5 million people die, while 5 million people are left permanently disabled. In this sense, the research to find new treatments should be accompanied with new therapies to combat neuronal death and to avoid developing cognitive impairment and dementia.

Phytocannabinoids are among the compounds that have been used by mankind for the longest period of history. Their beneficial effects such as pain regulation or neuroprotection are widely known and make them possible therapeutic agents with high potential.

These compounds bind cannabinoid receptors CB1 and CB2. Unfortunately, the psychoactive side effect has displaced them in the vast majority of areas. Thus, progress in the research and development of new compounds that show efficiency as neuroprotectors without this psychoactive effect is essential.

On the one hand, these compounds could selectively bind the CB2 receptor that does not show psychoactive effects and, in glia, has opened new avenues in this field of research, shedding new light on the use of cannabinoid receptors as therapeutic targets to combat neurodegenerative diseases such as Alzheimer’s, Parkinson’s disease, or stroke.

On the other hand, a new possibility lies in the formation of heteromers containing cannabinoid receptors. Heteromers are new functional units that show new properties compared to the individual protomers. Thus, they represent a new possibility that may offer the beneficial effects of cannabinoids devoid of the unwanted psychoactive effect.

Nowadays, the approval of a mixture of CBD (cannabidiol) and Δ9-THC (tetrahydrocannabinol) to treat the neuropathic pain and spasticity in multiple sclerosis or purified cannabidiol to combat pediatric epilepsy have opened new therapeutic possibilities in the field of cannabinoids and returned these compounds to the front line of research to treat pathologies as relevant as stroke.”

https://pubmed.ncbi.nlm.nih.gov/38928415/

“Phytocannabinoids not presenting psychoactive effects such as cannabidiol show an interesting potential to decrease neuroinflammation and neurodegeneration in animal models of hypoxia-ischemia, becoming a new promising therapy to improve stroke.”

https://www.mdpi.com/1422-0067/25/12/6708

Cannabidiol (CBD) Inhibits Foam Cell Formation via Regulating Cholesterol Homeostasis and Lipid Metabolism

Posted on by
Reply
pubmed logo

“Scope: The cannabidiol (CBD) in hemp oil has important pharmacological activities. Accumulating evidence suggests that CBD is beneficial in the cardiovascular system and has been applied as a health supplement for atherosclerosis. However, the mechanism remains unclear.

Methods and results: This study investigates the impact of CBD on foam cell formation, cholesterol homeostasis, and lipid metabolism in macrophages. CBD elevates the levels of peroxisome proliferator-activated receptor gamma (PPARγ) and its associated targets, such as ATP binding transporter A1/G1 (ABCA1/ABCG1), thus reducing foam cell formation, and increasing cholesterol efflux within macrophages. Notably, the upregulation of ABCA1 and ABCG1 expression induced by CBD is found to be attenuated by both a PPARγ inhibitor and PPARγ small interfering RNA (siRNA). Moreover, transfection of PPARγ siRNA results in a decrease in the inhibitory effect of CBD on foam cell formation and promotion of cholesterol efflux. Through lipidomics analysis, the study finds that CBD significantly reverses the enhancement of ceramide (Cer). Correlation analysis indicates a negative association between Cer level and the expression of ABCA1/ABCG1.

Conclusion: This study confirms that CBD can be an effective therapeutic candidate for atherosclerosis treatment by activating PPARγ, up-regulating ABCA1/ABCG1 expression, and down-regulating Cer level.”

https://pubmed.ncbi.nlm.nih.gov/38932553/

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202400154

Cannabidiol Protects against the Reinstatement of Oxycodone-Induced Conditioned Place Preference in Adolescent Male but Not Female Rats: The Role of MOR and CB1R

Posted on by
Reply
pubmed logo

“Cannabidiol (CBD), a phytocannabinoid, appeared to satisfy several criteria for a safe approach to preventing drug-taking behavior, including opioids. However, most successful preclinical and clinical results come from studies in adult males. We examined whether systemic injections of CBD (10 mg/kg, i.p.) during extinction of oxycodone (OXY, 3 mg/kg, i.p.) induced conditioned place preference (CPP) could attenuate the reinstatement of CPP brought about by OXY (1.5 mg/kg, i.p.) priming in adolescent rats of both sexes, and whether this effect is sex dependent. Accordingly, a priming dose of OXY produced reinstatement of the previously extinguished CPP in males and females. In both sexes, this effect was linked to locomotor sensitization that was blunted by CBD pretreatments. However, CBD was able to prevent the reinstatement of OXY-induced CPP only in adolescent males and this outcome was associated with an increased cannabinoid 1 receptor (CB1R) and a decreased mu opioid receptor (MOR) expression in the prefrontal cortex (PFC). The reinstatement of CCP in females was associated with a decreased MOR expression, but no changes were detected in CB1R in the hippocampus (HIP). Moreover, CBD administration during extinction significantly potentialized the reduced MOR expression in the PFC of males and showed a tendency to potentiate the reduced MOR in the HIP of females. Additionally, CBD reversed OXY-induced deficits of recognition memory only in males. These results suggest that CBD could reduce reinstatement to OXY seeking after a period of abstinence in adolescent male but not female rats. However, more investigation is required.”

https://pubmed.ncbi.nlm.nih.gov/38928357/

“In conclusion, our findings indicate that CBD is effective in preventing OXY seeking behavior after a period of abstinence in adolescent male, but not in female rats. This effect in males appears to be due to the interaction between CB1R and MOR. Further research is needed to determine whether the lack of effect in female adolescent rats is related to gonadal hormone status, dose of CBD, or other mechanisms, such as that, for example, of CB2R. It is important to investigate the mechanisms behind these sex differences, especially since previous research has shown that CBD reduces cue-induced cravings in humans with heroin use disorder.”

https://www.mdpi.com/1422-0067/25/12/6651

Cannabinoids’ Role in Modulating Central and Peripheral Immunity in Neurodegenerative Diseases

Posted on by
Reply
pubmed logo

“Cannabinoids (the endocannabinoids, the synthetic cannabinoids, and the phytocannabinoids) are well known for their various pharmacological properties, including neuroprotective and anti-inflammatory features, which are fundamentally important for the treatment of neurodegenerative diseases.

The aging of the global population is causing an increase in these diseases that require the development of effective drugs to be even more urgent. Taking into account the unavailability of effective drugs for neurodegenerative diseases, it seems appropriate to consider the role of cannabinoids in the treatment of these diseases.

To our knowledge, few reviews are devoted to cannabinoids’ impact on modulating central and peripheral immunity in neurodegenerative diseases. The objective of this review is to provide the best possible information about the cannabinoid receptors and immuno-modulation features, peripheral immune modulation by cannabinoids, cannabinoid-based therapies for the treatment of neurological disorders, and the future development prospects of making cannabinoids versatile tools in the pursuit of effective drugs.”

https://pubmed.ncbi.nlm.nih.gov/38928109/

“The increasing acceptance of cannabinoids caused novel preclinical research of neurodegenerative diseases, which was collected and analyzed in this review. These studies demonstrated the neuroprotective properties of many cannabinoids through various cellular and molecular pathways in neurodegenerative diseases. The strengthening connection between the periphery and the CNS in the context of neurodegenerative diseases, together with the extensive immune activities of cannabinoids in both arenas, shows the complexity of immune modulation and the enormous therapeutic potential of cannabinoids in neurodegenerative diseases, which are very difficult to manage.”

https://www.mdpi.com/1422-0067/25/12/6402