Effect of Cannabistilbene I in Attenuating Angiotensin II-Induced Cardiac Hypertrophy: Insights into Cytochrome P450s and Arachidonic Acid Metabolites Modulation

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“Introduction: This research investigated the impact of Cannabistilbene I on Angiotensin II (Ang II)-induced cardiac hypertrophy and its potential role in cytochrome P450 (CYP) enzymes and arachidonic acid (AA) metabolic pathways. Cardiac hypertrophy, a response to increased stress on the heart, can lead to severe cardiovascular diseases if not managed effectively. CYP enzymes and AA metabolites play critical roles in cardiac function and hypertrophy, making them important targets for therapeutic intervention. 

Methods: Adult human ventricular cardiomyocyte cell line (AC16) was cultured and treated with Cannabistilbene I in the presence and absence of Ang II. The effects on mRNA expression related to cardiac hypertrophic markers and CYP were analyzed using real-time polymerase chain reaction, while CYP protein levels were measured by Western blot analysis. AA metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). 

Results: Results showed that Ang II triggered hypertrophy, as evidenced by the increase in hypertrophic marker expression, and enlarged the cell surface area, effects that were alleviated by Cannabistilbene I. Gene expression analysis indicated that Cannabistilbene I upregulated CYP1A1, leading to increased enzymatic activity, as evidenced by 7-ethoxyresorufin-O-deethylase assay. Furthermore, LC-MS/MS analysis of AA metabolites revealed that Ang II elevated midchain (R/S)-hydroxyeicosatetraenoic acid (HETE) concentrations, which were reduced by Cannabistilbene I. Notably, Cannabistilbene I selectively increased 19(S)-HETE concentration and reversed the Ang II-induced decline in 19(S)-HETE, suggesting a unique protective role. 

Conclusion: This study provides new insights into the potential of Cannabistilbene I in modulating AA metabolites and reducing Ang II-induced cardiac hypertrophy, revealing a new candidate as a therapeutic agent for cardiac hypertrophy.”

https://pubmed.ncbi.nlm.nih.gov/39324890/

https://www.liebertpub.com/doi/10.1089/can.2024.0148

“Cannabistilbene I (CBG-I) is a naturally occurring derivative of the plant cannabis. It is a polyphenol compound found in the resinous glandular trichomes of the cannabis plant. CBG-I is known for its potent antioxidant, anti-inflammatory, and neuroprotective properties, making it a promising area of research in various fields.

Cannabistilbene I was first isolated and identified in 1975 by scientists from the University of Mississippi. It is a distinct compound from other cannabinoids and is found in different cannabis varieties. CBG-I is the precursor to THC, CBD, and other cannabinoids, which makes it essential in the biosynthesis of these compounds.”

https://www.smolecule.com/products/s579399


Cannabinoids as a Natural Alternative for the Management of Neuropathic Pain: A Systematic Review of Randomized Placebo-Controlled Trials

“Dysfunction or damage to the nervous system may develop into and result in a chronic pain condition known as neuropathic pain. Neuropathic pain is defined as the structural and functional alteration of the somatosensory component of the nervous system. The treatment of neuropathic pain is a complex endeavor, which often requires specialist care and intensive drug therapy. Recently, cannabinoids have emerged as an alternative and natural option for the treatment of chronic pain, with tetrahydrocannabinol (THC) and cannabidiol (CBD) being the most extensively studied neuroactive components. The therapeutic potential of cannabis remains largely underexplored, primarily due to its social stigma and the restrictions that are in place on its cultivation. The primary aim of this systematic review was to explore the therapeutic value of cannabinoids in the management of chronic pain and thus achieve an improved quality of life for those patients.

A systematic review of the literature published over the last two decades was performed using the following databases: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Turning research into practice (Trip), and Google Scholar. Studies that were completed and published between January 01, 2000 and August 31, 2024, in English language, were extracted and appraised. A combination of keywords and Boolean operators Cannabis OR Chronic Pain OR End of life OR Pain Management AND Drug therapy was employed for data extraction. The Cochrane risk-of-bias tool for randomized trials (RoB 2) was used for risk-of-bias assessment. The initial search resulted in 125282 articles; 86,781 of the articles were identified as duplicates and were removed from the primary analysis, and 38,501 abstracts were thus screened. Abstracts, case studies, reports, editorials, viewpoints, cross-sectional studies, cohort studies, case-control studies, case series, and letters to the editor/correspondence manuscripts (n =38,492) were furthermore excluded. Nine full-text articles were critically assessed and tested against the inclusion and exclusion criteria, and a further four articles were excluded with a total of five placebo-controlled randomized control studies being ultimately included in the final systematic review.

Compared to placebo, cannabinoids provided significant relief from chronic pain (33% vs 15%) as measured by the visual analog scale. The transdermal application of CBD led to a more pronounced reduction in sharp pain, according to the neuropathic pain scale. Minimal to no side effects were recorded, further highlighting the potential benefits of cannabinoids. 

The potential benefit of cannabinoids is that they are naturally derived drugs that have already been shown to have the potential to effectively decrease chronic pain with minimal side effects as compared to the standard drugs being used. The ability of cannabinoids to provide pain relief with minimal side effects and concurrently be a naturally derived product may potentially be a life-changing alternative that the pharmaceutical market is in dire need of.”

https://www.cureus.com/articles/297124-cannabinoids-as-a-natural-alternative-for-the-management-of-neuropathic-pain-a-systematic-review-of-randomized-placebo-controlled-trials#!/

The endocannabinoid system as a therapeutic target in neuropathic pain: a review

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“Introduction: This review highlights the critical role of the endocannabinoid system (ECS) in regulating neuropathic pain and explores the therapeutic potential of cannabinoids. Understanding the mechanisms of the ECS, including its receptors, endogenous ligands, and enzymatic routes, can lead to innovative treatments for chronic pain, offering more effective therapies for neuropathic conditions. This review bridges the gap between preclinical studies and clinical applications by emphasizing ECS modulation for better pain management outcomes.

Areas covered: A review mapped the existing literature on neuropathic pain and the effects of modulating the ECS using natural and synthetic cannabinoids. This analysis examined ECS components and their alterations in neuropathic pain, highlighting the peripheral, spinal, and supraspinal mechanisms. This review aimed to provide a thorough understanding of the therapeutic potential of cannabinoids in the management of neuropathic pain.

Expert opinion: Advances in cannabinoid research have shown significant potential for the management of chronic neuropathic pain. The study emphasizes the need for high-quality clinical trials and collaborative efforts among researchers, clinicians, and regulatory bodies to ensure safe and effective integration of cannabinoids into pain management protocols. Understanding the mechanisms and optimizing cannabinoid formulations and delivery methods are crucial for enhancing therapeutic outcomes.”

https://pubmed.ncbi.nlm.nih.gov/39317147/

“Research on the modulation of the endocannabinoid system in nervous tissue related to neuropathic pain reveals complex mechanisms of pain modulation. Dysregulation of the endocannabinoid system, microglial activation, and interactions between various signaling pathways contribute to the onset and persistence of neuropathic pain. Understanding these molecular and cellular processes is crucial for developing targeted therapies that leverage the endocannabinoid system to alleviate neuropathic pain.”

https://www.tandfonline.com/doi/full/10.1080/14728222.2024.2407824

“Smoked Cannabis Proven Effective In Treating Neuropathic Pain”

https://www.sciencedaily.com/releases/2007/10/071024141745.htm

Cannabidiol, a plant-derived compound, is an emerging strategy for treating cognitive impairments: comprehensive review of randomized trials

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“Background: Finding new strategies to treat cognitive disorders is a challenging task. Medication must defeat the blood-brain barrier. Cannabidiol (CBD), a non-intoxicating compound of the cannabis plant, has gained recognition as a nutraceutical for its potential effectiveness in treating anxiety, oxidative stress, convulsions, and inflammation. However, the dose, tolerable upper intake, formulation, administration routes, comorbidities, diet, and demographic factors to reverse cognitive impairments have not been completely explored. Trials using CBD as a primary intervention have been conducted to alleviate cognitive issues. This review evaluates the benefits of CBD supplementation, research design, formulations, and outcomes reported in randomized clinical trials.

Methods: An evidence-based systematic literature review was conducted using PUBMED and the Florida International University Research Library resources. Fourteen randomized trials were selected for review, and their designs and outcomes were compared conceptually and in the form of resume tables.

Results: CBD showed improvement in anxiety and cognitive impairments in 9 out of 16 analyzed trials. However, the variability could be justified due to the diversity of the trial designs, underpowered studies, assayed population, uncontrolled results for comorbidities, medications, severity of drug dependence, compliances, and adherences. Overall, oral single doses of 200 mg-1,500 mg or vaporized 13.75 mg of CBD were shown to be effective at treating anxiety and cognition with a good safety profile and no drug addiction behaviors. Conversely, results that did not have a significant effect on treating cognitive impairments can be explained by various factors such as THC or other abuse drugs masking effect, low dose, and unknown purity of CBD. Furthermore, CBD shows potential properties that can be tested in the future for Alzheimer’s disease.

Conclusion: As medical cannabis becomes more accessible, it is essential to understand whether medication rich in CBD exerts a beneficial effect on cognitive disorders. Our study concludes that CBD is a promising candidate for treating neurocognitive disorders; however, more studies are required to define CBD as a therapeutic candidate for managing cognitive disorders.”

https://pubmed.ncbi.nlm.nih.gov/39323633/

“Cannabidiol (CBD), a phytocannabinoid, is derived from the cannabis plant.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1403147/full

Proof of Concept for High-Dose Cannabidiol Pretreatment to Antagonize Opioid Induced Persistent Apnea

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“Using a mouse equivalent of FDA-approved cannabidiol (CBD) dosing, we found high dose CBD affects opioid induced persistent apnea (OIPA), the principal cause of opioid related fatalities.

CBD pretreatment mitigated respiratory depression from fentanyl in awake mice and significantly delayed OIPA onset in anesthetized mice, effective as the opioid antagonist naloxone.

The powerful effect of CBD pretreatment on OIPA suggests a novel therapeutic strategy to reduce fatal opioid overdose incidence.”

https://pubmed.ncbi.nlm.nih.gov/39314412/

https://www.biorxiv.org/content/10.1101/2024.09.13.612358v1

“Naloxone is a life-saving medication that can reverse an overdose from opioids—including heroin, fentanyl, and prescription opioid medications—when given in time.”

https://www.cdc.gov/stop-overdose/caring/naloxone.html#:~:text=What%20is%20naloxone%3F,use%20and%20small%20to%20carry.

Cannabidiol Modulation of Nicotine-Induced Toxicity: Assessing Effects on Behavior, Brain-Derived Neurotrophic Factor, and Oxidative Stress in C57BL/6 Male Mice

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“High doses of nicotine administered to rodents serve as a model for studying anxiety and test compounds’ potential anxiolytic effects. At these doses, anxiety in rodents is accompanied by disruption of brain-derived neurotrophic factor (BDNF). The endocannabinoids and nicotine modulate several central nervous system processes via their specific receptors, impacting locomotion, anxiety, memory, nociception, and reward.

Cannabidiol (CBD), an active ingredient of Cannabis sativa L., is devoid of psychoactive actions and has gained attention for its anxiolytic, antioxidant, and anti-inflammatory properties, among others. This work aims to examine the potential anxiety-reducing properties of CBD in a well-established experimental mouse model of anxiety-like behavior induced by high doses of nicotine on male C57BL/6 mice.

In this context, the open-field behavioral test was specially conducted to assess CBD’s effects on anxiety-like behavior and locomotion. Brain neuronal plasticity, modulated by BDNF, along with a diverse array of blood’s metabolic markers, was examined as a means of evaluating systemic toxicity under various treatments. Finally, oxidative stress was evaluated through the measurement of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), while pro-inflammatory cytokine assessments were conducted to evaluate redox status and immune system function.

Our research suggests that CBD shows potential in reducing anxiety-like behaviors induced by high doses of nicotine, by mitigating changes in BDNF protein levels in cerebral hemispheres and cerebellum. At the same time, CBD targets specific liver enzymes, maintains tissue’s systemic toxicity (i.e., renal, kidney, and pancreatic), balances redox status (SOD, GSH, and MDA), and regulates the secretion of pro-inflammatory cytokines (TNF-alpha and IL-6).”

https://pubmed.ncbi.nlm.nih.gov/39297526/

https://onlinelibrary.wiley.com/doi/10.1002/jnr.25384

[Transepithelial transport in vivo and in vitro and anti-inflammatory activity of cannabidiol]

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“This study used Caco-2 cells and normal rats to investigate the in vitro absorption characteristics and in vivo pharmacokinetic characteristics of cannabidiol(CBD) and explore the anti-inflammatory mechanism of CBD. The safe concentration range of CBD was determined by the CCK-8 assay, and then the effects of time, concentration, temperature, endocytosis inhibitors, and transport inhibitors on the transepithelial absorption and transport of CBD were assessed. The blood drug concentration was measured at different time points after oral administration in rats for pharmacokinetic profiling, and the pharmacokinetic parameters were calculated. The Caco-2 cell model of inflammation injury was established with lipopolysaccharide(LPS). The effects of CBD on lactate dehydrogenase(LDH) activity, transendothelial electrical resistance(TEER), and levels of inflammatory cytokines of the modeled cells were exami-ned, on the basis of which the anti-inflammatory mechanism of CBD was deciphered.

The results showed that within the concentration range tested in this study, the CBD uptake by Caco-2 cells reached saturation at the time point of 2 h. Moreover, the CBD uptake was positively correlated with concentration and temperature and CBD could be endocytosed into the cells. CBD could penetrate Caco-2 cells through active transport pathways involving multidrug resistance-associate protein 2(MRP2) and breast cancer resistance protein(BCRP), while the addition of P-gp inhibitors had no effect on CBD transport. Rats exhibited rapid absorption of CBD, with the peak time(t_(max)) of(1.00±0.11) h, and fast elimination of CBD, with a half-life(t_(1/2)) of only(1.86±0.16) h. In addition, CBD significantly ameliorated the increased LDH activity and decreased TEER that were caused by inflammatory response. It maintained the intestinal barrier by down-regulating the expression of pro-inflammatory cytokines interleukin-8(IL-8), interleukin-1 beta(IL-1β) and tumor necrosis factor-α(TNF-α), thus exerting anti-inflammatory effects.”

https://pubmed.ncbi.nlm.nih.gov/39307812/

P2X7 receptors from the perspective of NLRP3 inflammasome pathway in depression: Potential role of cannabidiol

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“Many patients with depressive disorder do not respond to conventional antidepressant treatment. There is an ongoing interest in investigating potential mechanisms of treatment resistance in depression to provide alternative treatment options involving inflammatory mechanisms.

Increasing evidence implicates the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome as a critical factor in neuroinflammation. ATP-induced P2X7 receptor (P2X7R) activation is a major trigger for inflammation, activating the canonical NLRP3 inflammatory cascade.

Psychosocial stress, the primary environmental risk factor for depression, is associated with changes in ATP-mediated P2X7R signaling.

Depression and stress response can be alleviated by Cannabidiol (CBD).

CBD has an anti-inflammatory activity related to the regulation of NLRP3 inflammasome activation. However, CBD’s effects on the inflammasome pathway are poorly understood in central nervous system (CNS) cells, including microglia, astrocytes, and neurons.

This review will emphasize some findings for neuroinflammation and NLRP3 inflammasome pathway involvement in depression, particularly addressing the ATP-induced P2X7R activation. Moreover, we will underline evidence for the effect of CBD on depression and address its potential impacts on neuroinflammation through the NLRP3 inflammasome cascade.”

https://pubmed.ncbi.nlm.nih.gov/39296605/

“Highlights

  • •Neuroinflammation plays an important role in the development of depressive disorder.
  • •The NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome contributes to the pathogenesis of depression.
  • •ATP-induced P2X7 receptor (P2X7R) activation triggers the canonical NLRP3 inflammatory cascade.
  • •P2X7R antagonists have potential antidepressant effects.
  • •CBD has anti-inflammatory properties related to the regulation of NLRP3 inflammasome activation.”

https://www.sciencedirect.com/science/article/pii/S2666354624001315?via%3Dihub


Unleashing the therapeutic role of cannabidiol in dentistry

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“Cannabidiol (CBD) found in Cannabis sativa is a non-psychoactive compound which is capable of binding to CB1 and CB2 receptors. CBD has recently gained interest in dentistry although it has not been explored sufficiently yet.

The therapeutic effects of CBD include anti-inflammatory, analgesic, antioxidant, biological and osteoinductive properties. The aim of this review is to highlight these effects with respect to various oral conditions and shed light on the current limitations and prospects for the use of CBD in maintaining oral health.”

https://pubmed.ncbi.nlm.nih.gov/39296277/

“CBD are potent non-psychoactive drug which when used in appropriate proportions under proper guidelines hold the potential to drastically change the current state of dental sciences. However, future researches are imperative focusing on the nature, mechanism, formulations as well as modes of administration to understand this drug thoroughly. Nonetheless, due to its properties such as anti-inflammation, antioxidation, biological nature, analgesia as well as osteoinduction; it is a drug with promising future in dentistry.”

https://www.sciencedirect.com/science/article/pii/S2212426824001258?via%3Dihub

Cannabidiol for the Treatment of Cervical Spondyloarthritis-Related Pain: A Case Report

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“Spondyloarthritis (SA) is a chronic inflammatory disease that predominantly affects the spinal column. SA-related pain can be intense, persistent, and disabling. Studies with cannabis have been conducted involving patients with refractory epilepsy, multiple sclerosis, Parkinson’s disease, sleep disorders, and chronic pain.

Cannabidiol is the major non-psychotropic component of cannabis, has anti-inflammatory and analgesic properties, and exerts anxiolytic and mood-stabilizing effects. This paper reports a case of a 72-year-old male with SA, with mild stenoses of the spinal canal at C4-C5 and C5-C6 and stenoses of the left neural foramina at C3-C4, C4-C5, C5-C6, and C6-C7.

The use of cannabidiol in our patient achieved satisfactory results in the control of pain related to cervical spondyloarthritis.”

https://pubmed.ncbi.nlm.nih.gov/39295690/

https://www.cureus.com/articles/278440-cannabidiol-for-the-treatment-of-cervical-spondyloarthritis-related-pain-a-case-report#!/