RESUMEN

In the setting of increasing patient-reported cannabidiol (CBD) usage in the dermatologic setting, it is of great importance that clinicians become aware of potential medication interactions that may arise from cannabidiol usage in order to ensure safe and efficacious medication therapy. This brief review aimed to bring awareness to the mechanism of CBD while highlighting potential interactions between CBD and medication therapy for commonly encountered dermatologic conditions, including acne, allergic contact dermatitis, atopic dermatitis, pruritus, skin aging, skin cancer, and psoriasis.

Asunto(s)

Cannabidiol , Interacciones Farmacológicas , Enfermedades de la Piel , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Cannabidiol/efectos adversos , Humanos , Enfermedades de la Piel/tratamiento farmacológico , Fármacos Dermatológicos/farmacología , Fármacos Dermatológicos/uso terapéutico , Fármacos Dermatológicos/efectos adversos

RESUMEN

Alzheimer's disease (AD) is the leading form of dementia, characterized by the accumulation and aggregation of amyloid in brain. Transient receptor potential vanilloid 2 (TRPV2) is an ion channel involved in diverse physiopathological processes, including microglial phagocytosis. Previous studies suggested that cannabidiol (CBD), an activator of TRPV2, improves microglial amyloid-ß (Aß) phagocytosis by TRPV2 modulation. However, the molecular mechanism of TRPV2 in microglial Aß phagocytosis remains unknown. In this study, we aimed to investigate the involvement of TRPV2 channel in microglial Aß phagocytosis and the underlying mechanisms. Utilizing human datasets, mouse primary neuron and microglia cultures, and AD model mice, to evaluate TRPV2 expression and microglial Aß phagocytosis in both in vivo and in vitro. TRPV2 was expressed in cortex, hippocampus, and microglia.Cannabidiol (CBD) could activate and sensitize TRPV2 channel. Short-term CBD (1 week) injection intraperitoneally (i.p.) reduced the expression of neuroinflammation and microglial phagocytic receptors, but long-term CBD (3 week) administration (i.p.) induced neuroinflammation and suppressed the expression of microglial phagocytic receptors in APP/PS1 mice. Furthermore, the hyper-sensitivity of TRPV2 channel was mediated by tyrosine phosphorylation at the molecular sites Tyr(338), Tyr(466), and Tyr(520) by protein tyrosine kinase JAK1, and these sites mutation reduced the microglial Aß phagocytosis partially dependence on its localization. While TRPV2 was palmitoylated at Cys 277 site and blocking TRPV2 palmitoylation improved microglial Aß phagocytosis. Moreover, it was demonstrated that TRPV2 palmitoylation was dynamically regulated by ZDHHC21. Overall, our findings elucidated the intricate interplay between TRPV2 channel regulated by tyrosine phosphorylation/dephosphorylation and cysteine palmitoylation/depalmitoylation, which had divergent effects on microglial Aß phagocytosis. These findings provide valuable insights into the underlying mechanisms linking microglial phagocytosis and TRPV2 sensitivity, and offer potential therapeutic strategies for managing AD.

Asunto(s)

Péptidos beta-Amiloides , Lipoilación , Ratones Transgénicos , Microglía , Fagocitosis , Canales Catiónicos TRPV , Tirosina , Animales , Ratones , Microglía/metabolismo , Microglía/efectos de los fármacos , Canales Catiónicos TRPV/metabolismo , Péptidos beta-Amiloides/metabolismo , Fagocitosis/efectos de los fármacos , Humanos , Fosforilación/efectos de los fármacos , Tirosina/metabolismo , Lipoilación/efectos de los fármacos , Células Cultivadas , Enfermedad de Alzheimer/metabolismo , Cannabidiol/farmacología , Ratones Endogámicos C57BL , Canales de Calcio

RESUMEN

In T-cell acute lymphoblastic leukemia (T-ALL), more than 50% of cases display autoactivation of Notch1 signaling, leading to oncogenic transformation. We have previously identified a specific chemovar of Cannabis that induces apoptosis by preventing Notch1 maturation in leukemia cells. Here, we isolated three cannabinoids from this chemovar that synergistically mimic the effects of the whole extract. Two were previously known, cannabidiol (CBD) and cannabidivarin (CBDV), whereas the third cannabinoid, which we termed 331-18A, was identified and fully characterized in this study. We demonstrated that these cannabinoids act through cannabinoid receptor type 2 and TRPV1 to activate the integrated stress response pathway by depleting intracellular Ca2+. This is followed by increased mRNA and protein expression of ATF4, CHOP, and CHAC1, which is hindered by inhibiting the upstream initiation factor eIF2α. The increased abundance of CHAC1 prevents Notch1 maturation, thereby reducing the levels of the active Notch1 intracellular domain, and consequently decreasing cell viability and increasing apoptosis. Treatment with the three isolated molecules resulted in reduced tumor size and weight in vivo and slowed leukemia progression in mice models. Altogether, this study elucidated the mechanism of action of three distinct cannabinoids in modulating the Notch1 pathway, and constitutes an important step in the establishment of a new therapy for treating NOTCH1-mutated diseases and cancers such as T-ALL.

Asunto(s)

Cannabinoides , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Receptor Notch1 , Receptor Notch1/metabolismo , Receptor Notch1/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Animales , Ratones , Humanos , Cannabinoides/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Cannabidiol/farmacología , Mutación

RESUMEN

Pain is an unpleasant sensory and emotional experience. Adequate pain control is often challenging, particularly in patients with chronic pain. Despite advances in pain management, drug addiction, overtreatment, or substance use disorders are not rare. Hence the need for further studies in the field. The substantial progress made over the last decade has revealed genes, signalling pathways, molecules, and neuronal networks in pain control thus opening new clinical perspectives in pain management. In this respect, data on the epigenetic modulation of opioid and cannabinoid receptors, key actors in the modulation of pain, offered new perspectives to preserve the activity of opioid and endocannabinoid systems to increase the analgesic efficacy of opioid- and cannabinoid-based drugs. Similarly, upcoming data on cannabidiol (CBD), a non-psychoactive cannabinoid in the marijuana plant Cannabis sativa, suggests analgesic, anti-inflammatory, antioxidant, anticonvulsivant and ansiolitic effects and supports its potential application in clinical contexts such as cancer, neurodegeneration, and autoimmune diseases but also in health and fitness with potential use in athletes. Hence, in this review article, we summarize the emerging epigenetic modifications of opioid and cannabinoid receptors and focus on CBD as an emerging non-psychoactive cannabinoid in pain management in clinical practice, health, and fitness.

Asunto(s)

Analgésicos Opioides , Cannabinoides , Receptores de Cannabinoides , Humanos , Analgésicos Opioides/uso terapéutico , Analgésicos Opioides/farmacología , Cannabinoides/uso terapéutico , Cannabinoides/farmacología , Receptores de Cannabinoides/metabolismo , Animales , Dolor/tratamiento farmacológico , Dolor/metabolismo , Cannabidiol/uso terapéutico , Cannabidiol/farmacología , Receptores Opioides/metabolismo , Epigénesis Genética/efectos de los fármacos , Manejo del Dolor/métodos , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/metabolismo , Endocannabinoides/metabolismo

RESUMEN

In recent years, extensive research has focused on cannabidiol (CBD), a well-studied non-psychoactive component of the plant-derived cannabinoids. CBD has shown significant therapeutic potential for treating various diseases and disorders, including antioxidants and anti-inflammatory effects. Due to the promising therapeutic effect of CBD in a wide variety of diseases, synthetic derivatization of this compound has attracted the attention of drug discovery in both industry and academia. In the current research, we focused on the derivatization of CBD by introducing Schiff base moieties, particularly (thio)-semicarbazide and aminoguanidine motifs, at the 3-position of the olivetolic ring. We have designed, synthesized, and characterized new derivatives based on CBD's framework, specifically aminoguanylhydrazone- and (thio)-semicarbazones-CBD-aldehyde compounds. Their antioxidant potential was assessed using FRAP and DPPH assays, alongside an evaluation of their effect on LDL oxidation induced by Cu2+ and AAPH. Our findings suggest that incorporating the thiosemicarbazide motif into the CBD framework produces a potent antioxidant, warranting further investigation.

Asunto(s)

Antioxidantes , Cannabidiol , Diseño de Fármacos , Cannabidiol/química , Cannabidiol/farmacología , Cannabidiol/síntesis química , Antioxidantes/síntesis química , Antioxidantes/farmacología , Antioxidantes/química , Oxidación-Reducción , Semicarbacidas/química , Semicarbacidas/síntesis química , Semicarbacidas/farmacología , Lipoproteínas LDL/metabolismo , Bases de Schiff/química , Bases de Schiff/farmacología , Bases de Schiff/síntesis química

RESUMEN

BACKGROUND: Cannabinoids such as cannabidiol (CBD) exhibit anti-inflammatory properties and have the potential to act as a therapeutic following mild traumatic brain injury. There is limited evidence available on the pharmacological, physiological and psychological effects of escalating CBD dosages in a healthy, male, university athlete population. Furthermore, no dosing regimen for CBD is available with implications of improving physiological function. This study will develop an optimal CBD dose based on the pharmacokinetic data in contact-sport athletes. The physiological and psychological data will be correlated to the pharmacokinetic data to understand the mechanism(s) associated with an escalating CBD dose. METHODS/DESIGN: Forty participants will receive escalating doses of CBD ranging from 5 mg CBD/kg/day to 30 mg CBD/kg/day. The CBD dose is escalated every two weeks in increments of 5 mg CBD/kg/day. Participants will provide blood for pharmacological assessments at each of the 10 visits. Participants will complete a physiological assessment at each of the visits, including assessments of cerebral hemodynamics, blood pressure, electrocardiogram, seismocardiogram, transcranial magnetic stimulation, and salivary analysis for genomic sequencing. Finally, participants will complete a psychological assessment consisting of sleep, anxiety, and pain-related questionnaires. DISCUSSION: This study will develop of an optimal CBD dose based on pharmacological, physiological, and psychological properties for future use during contact sport seasons to understand if CBD can help to reduce the frequency of mild traumatic injuries and enhance recovery. TRIAL REGISTRATION: Clinicaltrials.gov: NCT06204003.

Asunto(s)

Cannabidiol , Cannabidiol/administración & dosificación , Cannabidiol/farmacología , Cannabidiol/farmacocinética , Humanos , Masculino , Adulto Joven , Adulto , Relación Dosis-Respuesta a Droga , Adolescente , Presión Sanguínea/efectos de los fármacos

RESUMEN

Mutations in mitochondrial energy-producing genes lead to a heterogeneous group of untreatable disorders known as primary mitochondrial diseases (MD). Leigh syndrome (LS) is the most common pediatric MD and is characterized by progressive neuromuscular affectation and premature death. Here, we show that daily cannabidiol (CBD) administration significantly extends lifespan and ameliorates pathology in two LS mouse models, and improves cellular function in fibroblasts from LS patients. CBD delays motor decline and neurodegenerative signs, improves social deficits and breathing abnormalities, decreases thermally induced seizures, and improves neuropathology in affected brain regions. Mechanistically, we identify peroxisome proliferator-activated receptor gamma (PPARγ) as a key nuclear receptor mediating CBD's beneficial effects, while also providing proof of dysregulated PPARγ expression and activity as a common feature in both mouse neurons and fibroblasts from LS patients. Taken together, our results provide the first evidence for CBD as a potential treatment for LS.

Asunto(s)

Cannabidiol , Enfermedades Mitocondriales , PPAR gamma , Animales , Femenino , Humanos , Masculino , Ratones , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Modelos Animales de Enfermedad , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Enfermedad de Leigh/tratamiento farmacológico , Enfermedad de Leigh/metabolismo , Enfermedad de Leigh/genética , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , PPAR gamma/metabolismo , PPAR gamma/genética

RESUMEN

The aim of this study was to determine the antiviral activity of cannabidiol (CBD) against SARS-CoV-2 infection. CBD is the second most studied cannabinoid obtained from Cannabis plants. We investigated the potential use of CBD, which has so far proven to have a positive effect on different diseases, in the SARS-CoV-2 infection. To test this, in vivo studies were carried out using K18-hACE2 transgenic mice. To reveal the potential therapeutic effect of the CBD at the histopathological and molecular level challenge experiments were performed. The study was designed with two groups (n = 10) and in the treatment group animals were infected with SARS-CoV-2 virus strain B.1.1.7 alpha before the administration of CBD. While the disease progressed and resulted in death in the control group that was infected by the virus alone, it was observed that the infection slowed down and the survival rate increased in the mice treated with CBD along with the virus. In this study, K18-hACE2 transgenic mice infected with the wild SARS-CoV-2 virus were used to investigate and prove the antiviral activity of CBD.

Asunto(s)

Enzima Convertidora de Angiotensina 2 , Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Cannabidiol , SARS-CoV-2 , Animales , Humanos , Ratones , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Antivirales/farmacología , Antivirales/uso terapéutico , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , COVID-19/virología , COVID-19/patología , Modelos Animales de Enfermedad , Pulmón/virología , Pulmón/patología , Pulmón/efectos de los fármacos , Ratones Transgénicos , SARS-CoV-2/efectos de los fármacos , Carga Viral/efectos de los fármacos

RESUMEN

Athlete performance and post-load recovery can be considered one of the most important and actively discussed topics in professional sport. One substance aimed at improving performance is cannabidiol (CBD), which has been actively gaining popularity with several studies published in recent years. The PubMed, Scopus, and Cochrane Library databases were searched from inception to April 2024 according to PRISMA recommendations to identify studies on the effects of CBD on exercise capacity and post-load recovery. An initial search identified 901 publications, of which seven fully met the inclusion criteria. Current evidence supports a limited beneficial effect of CBD on a number of physiological parameters, such as VO2, mean power, and relative mean power. At the same time, there were limited data on the beneficial effects of CBD on strength parameters (including vertical jump, counter movement jump, one repetition max bench press, and barbell back squat) and post-load recovery. Notably, most of the studies included in the analysis were conducted between 2021 and 2024, indicating a growing interest among researchers in the use of CBD in healthy, physically active individuals. Further studies are needed to assess the safety of different CBD administration protocols in professional athletes.

Asunto(s)

Rendimiento Atlético , Cannabidiol , Cannabidiol/farmacología , Cannabidiol/administración & dosificación , Humanos , Rendimiento Atlético/fisiología , Atletas , Ejercicio Físico/fisiología , Masculino , Fuerza Muscular/efectos de los fármacos , Femenino , Adulto

RESUMEN

BACKGROUND: Cannabidiol (CBD), the major non-psychoactive component of cannabis, exhibits anti-inflammatory properties, but less is known about the immunomodulatory potential of CBD on activated natural killer (NK) cells and/or their targets. Many tumor cells present heat shock protein 70 (Hsp70) on their cell surface in a tumor-specific manner and although a membrane Hsp70 (mHsp70) positive phenotype serves as a target for Hsp70-activated NK cells, a high mHsp70 expression is associated with tumor aggressiveness. This study investigated the immuno-modulatory potential of CBD on NK cells stimulated with TKD Hsp70 peptide and IL-2 (TKD+IL-2) and also on HCT116 p53wt and HCT116 p53-/- colorectal cancer cells exhibiting high and low basal levels of mHsp70 expression. RESULTS: Apart from an increase in the density of NTB-A and a reduced expression of LAMP-1, the expression of all other activatory NK cell receptors including NKp30, NKG2D and CD69 which are significantly up-regulated after stimulation with TKD+IL-2 remained unaffected after a co-treatment with CBD. However, the release of major pro-inflammatory cytokines by NK cells such as interferon-γ (IFN-γ) and the effector molecule granzyme B (GrzB) was significantly reduced upon CBD treatment. With respect to the tumor target cells, CBD significantly reduced the elevated expression of mHsp70 but had no effect on the low basal mHsp70 expression. Expression of other NK cell ligands such as MICA and MICB remained unaffected, and the NK cell ligands ULBP and B7-H6 were not expressed on these target cells. Consistent with the reduced mHsp70 expression, treatment of both effector and target cells with CBD reduced the killing of high mHsp70 expressing tumor cells by TKD+IL-2+CBD pre-treated NK cells but had no effect on the killing of low mHsp70 expressing tumor cells. Concomitantly, CBD treatment reduced the TKD+IL-2 induced increased release of IFN-γ, IL-4, TNF-α and GrzB, but CBD had no effect on the release of IFN-α when NK cells were co-incubated with tumor target cells. CONCLUSION: Cannabidiol (CBD) may potentially diminish the anti-tumor effectiveness of TKD+IL-2 activated natural killer (NK) cells.

Asunto(s)

Cannabidiol , Proteínas HSP70 de Choque Térmico , Células Asesinas Naturales , Activación de Linfocitos , Humanos , Cannabidiol/farmacología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Proteínas HSP70 de Choque Térmico/metabolismo , Células HCT116 , Factores Inmunológicos/farmacología , Interleucina-2/metabolismo , Interleucina-2/inmunología , Granzimas/metabolismo , Interferón gamma/metabolismo , Interferón gamma/inmunología , Línea Celular Tumoral , Citotoxicidad Inmunológica/efectos de los fármacos

RESUMEN

Inflammation plays a critical role in the development of numerous diseases. Cannabidiol (CBD), found in hemp, exhibits significant pharmacological activities. Accumulating evidence suggests that CBD has anti-inflammatory and cardiovascular protection effects, but the potential mechanisms require further exploration. In this study, we aimed to reveal the mechanisms of CBD against high-fat, high-cholesterol (HFC) diet-induced inflammation combining metabolomics with network pharmacology. First, plasma lipidomics results indicated that oxidized lipids could serve as potential biomarkers for HFC diet-induced inflammation, and CBD reversed the elevated levels of oxidized lipids. The HFC diet was also found to enhance intestinal permeability, facilitating the entry of lipopolysaccharides (LPSs) into the circulatory system and subsequently increasing systemic inflammation. Additionally, cell metabolomic results indicated that CBD could reverse 10 important differential metabolites in LPS-induced RAW 264.7 cells. Using network pharmacology, we identified 49 core targets, and enrichment analysis revealed that arachidonic acid was the most significantly affected by CBD, which was closely associated with inflammation. Further integrated analysis focused on three key targets, including PTGS2, ALOX5, and ALOX15. Molecular docking showed high affinities between key targets and CBD, and qPCR further demonstrated that CBD could reverse the mRNA expression of these key targets in RAW 264.7 cells. Collectively, this finding integrates lipidomics and metabolomics with network pharmacology to elucidate the anti-inflammatory effects of CBD and validates key therapeutic targets.

Asunto(s)

Antiinflamatorios , Cannabidiol , Dieta Alta en Grasa , Inflamación , Lipidómica , Metabolómica , Ratones Endogámicos C57BL , Farmacología en Red , Animales , Cannabidiol/farmacología , Ratones , Dieta Alta en Grasa/efectos adversos , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/química , Células RAW 264.7 , Humanos , Colesterol/metabolismo , Simulación del Acoplamiento Molecular , Araquidonato 5-Lipooxigenasa/metabolismo , Araquidonato 5-Lipooxigenasa/genética , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo

RESUMEN

BACKGROUND: Endometriosis is associated with a wide variety of signs and symptoms and can lead to infertility, embryo death, and even miscarriage. Although the exact pathogenesis and etiology of endometriosis is still unclear, it has been shown that it has a chronic inflammatory nature and angiogenesis is also involved in it. OBJECTIVE: This review aims to explore the role of inflammation and angiogenesis in endometriosis and suggest a potential treatment targeting these pathways. FINDINGS: Among the pro-inflammatory cytokines, studies have shown solid roles for interleukin 1ß (IL-ß), IL-6, and tumor necrosis factor α (TNF-α) in the pathogenesis of this condition. Other than inflammation, angiogenesis, the formation of new blood vessels from pre-existing capillaries, is also involved in the pathogenesis of endometriosis. Among angiogenic factors, vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), transforming growth factor ß1 (TGF-ß1), and matrix metalloproteinases (MMPs) are more essential in the pathogenesis of endometriosis. Interestingly, it has been shown that inflammation and angiogenesis share some similar pathways with each other that could be potentially targeted for treatment of diseases caused by these two processes. Cannabidiol (CBD) is a non-psychoactive member of cannabinoids which has well-known and notable anti-inflammatory and antiangiogenic properties. This agent has been shown to decrease IL-1ß, IL-6, TNF-α, VEGF, TGFß, and MMPs in different animal models of diseases. CONCLUSION: It seems that CBD could be a possible treatment for endometriosis due to its anti-inflammatory and antiangiogenic activity, however, further studies are needed.

Asunto(s)

Cannabidiol , Endometriosis , Inflamación , Neovascularización Patológica , Endometriosis/tratamiento farmacológico , Endometriosis/patología , Femenino , Humanos , Cannabidiol/uso terapéutico , Cannabidiol/farmacología , Neovascularización Patológica/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Animales , Citocinas/metabolismo , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , Angiogénesis

RESUMEN

Cannabidiol (CBD) is a non-psychoactive drug extracted from marijuana. It is well established that CBD attenuates the reinforcing effects of drugs of abuse, although its mechanism of action is not fully understood. The current study tries to clarify the role of D1-like dopamine receptors (D1R) in the ventral tegmental area (VTA) in the inhibitory effects of the CBD on the acquisition and expression of methamphetamine (METH)-conditioned place preference (CPP). In the CPP training, adult male Wistar rats were conditioned with subcutaneous administration of METH (1 mg/kg) for five days. Three groups of animals were treated with multiple doses of SCH23390 (as a D1R antagonist; 0.25, 1, and 4 µg/0.3 µl saline) in the VTA, respectively, before intracerebroventricular (ICV) injection of CBD (10 µg/5 µl DMSO) in the acquisition phase. In the second experiment of the study, rats received SCH23390 in the VTA before ICV administration of CBD (50 µg/5 µl DMSO) in the expression of METH CPP. Here, the current study demonstrated that CBD inhibits the acquisition and expression of METH CPP, while microinjection of D1R antagonists (1 and 4 µg) into the VTA significantly reduced CBD's suppressive effect on the acquisition and expression of METH place preference. Furthermore, this research demonstrated that either SCH23390 or CBD alone does not lead to place preference in the CPP paradigm. Based on these data, this study suggests that pharmacological manipulations of D1R may alter the CBD's effect on METH-conditioned preference.

Asunto(s)

Benzazepinas , Cannabidiol , Antagonistas de Dopamina , Metanfetamina , Ratas Wistar , Receptores de Dopamina D1 , Área Tegmental Ventral , Animales , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismo , Metanfetamina/farmacología , Masculino , Cannabidiol/farmacología , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D1/metabolismo , Benzazepinas/farmacología , Ratas , Antagonistas de Dopamina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Relación Dosis-Respuesta a Droga , Condicionamiento Psicológico/efectos de los fármacos

RESUMEN

BACKGROUND: Spasticity is a common and potentially debilitating symptom of multiple sclerosis (MS) with a highly variable presentation. Understanding, quantifying, and managing MS-associated spasticity (MSS) is a challenge for research and in clinical practice. The tetrahydrocannabinol:cannabidiol oromucosal spray nabiximols has demonstrated beneficial effects in the treatment of MSS in clinical studies as well as real-world observational studies, and is approved for the treatment of MSS in 29 countries globally. Most randomized studies evaluated the efficacy of nabiximols using the change in average daily spasticity scores reported by patients using the spasticity Numeric Rating Scale as a primary endpoint. This study, RELEASE MSS1 (NCT04657666), was conducted using a prespecified primary endpoint of change in spastic muscle tone (Modified Ashworth Scale Lower Limb Muscle Tone-6 [MAS LLMT-6]) to corroborate the efficacy of nabiximols as adjunctive therapy observed with the patient-measured spasticity Numeric Rating Scale primary endpoint in the previous pivotal studies. METHODS: This was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 2-treatment, 2-period, crossover trial. Because of the prevalence and functional impact of lower limb spasticity on the individual patient's overall experience of MS spasticity, the MAS LLMT-6 was derived from the clinician-rated MAS. The MAS LLMT-6 is the average transformed MAS score of 6 muscle groups (knee flexors, knee extensors, and ankle plantar flexors; all assessed bilaterally). Secondary measures included MAS LLMT-4 scores, defined as the average of the 4 individual MAS-transformed scores of knee flexors and knee extensors bilaterally. Patients had a diagnosis of MS and an untransformed MAS score of at least 2 in ≥2 of 6 LLMT-6 muscle groups despite current treatment with ≥1 of the following oral antispasticity agents: baclofen, tizanidine, or dantrolene. Eligible participants were randomly assigned to 1 of 2 treatment sequences. Each treatment sequence consisted of two treatment periods, each consisting of a 14-day dose titration phase followed by a 7-day dose maintenance phase. RESULTS: Of 68 patients enrolled, 33 were assigned to nabiximols followed by placebo and 35 were assigned to placebo followed by nabiximols. Least squares mean changes in MAS LLMT-6 scores from baseline to day 21 were -0.23 for nabiximols and -0.26 for placebo; the least squares mean treatment difference in MAS LLMT-6 scores for nabiximols versus placebo was 0.04, which was not statistically significant (P = 0.7152). Mean changes in MAS LLMT-4 scores from baseline to day 21 also were not significantly different between the nabiximols and placebo groups. Safety results in this study were consistent with the known safety profile of nabiximols in patients with MSS. CONCLUSION: Despite the established efficacy of nabiximols in MSS observed using patient-reported measures, the primary endpoint was not met in this study. The findings from this study reflect and emphasize some of the challenges in the evaluation and treatment of MS spasticity. CLINICAL TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): : NCT04657666.

Asunto(s)

Cannabidiol , Dronabinol , Combinación de Medicamentos , Esclerosis Múltiple , Espasticidad Muscular , Humanos , Espasticidad Muscular/tratamiento farmacológico , Espasticidad Muscular/etiología , Cannabidiol/administración & dosificación , Cannabidiol/farmacología , Dronabinol/administración & dosificación , Dronabinol/farmacología , Método Doble Ciego , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Masculino , Vaporizadores Orales , Femenino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud

RESUMEN

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the main components of Cannabis sativa plants, have attracted a significant amount of attention due to their biological activities. This study identified GPR18 as the target of partial agonist CBD activating the p42/p44 MAPK pathway leading to migration of endometrial epithelial cells. Induced fit docking (IFD) showed that the affinity of THC for GPR18 is higher than that of CBD, and molecular dynamics (MD) simulations showed that CBD-GPR18 complexes at 130/200 ns might have stable conformations, potentially activating GPR18 by changing the distances of key residues in its active pocket. In contrast, THC maintains "metastable" conformations, generating a "shrinking space" leading to full agonism of THC by adding mechanical constraints in GPR18's active pocket. Steered molecular dynamics (SMD) revealed GPR18's active pocket was influenced more by CBD's partial agonism compared with THC. This combined IFD-MD-SMD method may be used to explain the mechanism of activation of partial or full agonists of GPR18.

Asunto(s)

Cannabidiol , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Receptores Acoplados a Proteínas G , Cannabidiol/farmacología , Cannabidiol/química , Cannabidiol/metabolismo , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Dronabinol/farmacología , Dronabinol/química , Dronabinol/metabolismo , Dronabinol/análogos & derivados , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Movimiento Celular/efectos de los fármacos , Femenino

RESUMEN

Atopic dermatitis (AD) is a highly prevalent chronic skin disease. Anti-inflammatory and antipruritic emollients (emollients plus) with excellent cosmetic properties may alleviate AD-related symptoms and reduce the number of exacerbations. To screen for herbal extracts with potent anti-inflammatory and antioxidative potential in human skin cell cultures. Ginger extract and synthetic cannabidiol (CBD) were identified and combined in the cosmetic product BNO 3731, which was evaluated in a randomized clinical trial. Preclinical: anti-inflammatory effects of ginger extract, synthetic CBD and a combination thereof were evaluated in human skin cell cultures by analysing nuclear factor κB activation, release of inflammatory cytokines and endocannabinoid production. Clinical: BNO 3731 was studied in a clinical trial comprising 44 AD patients (adults and children) and compared to a benchmark product over a treatment duration of five days. Symptom severity was evaluated by objective and subjective dermatological assessments as well as physiological skin parameters. Itch intensity was assessed using a numerical rating scale (NRS-11). Preclinical: Ginger extract and synthetic CBD exhibited potent anti-inflammatory and antioxidative effects in vitro which were associated with elevated concentrations of the endocannabinoid, anandamide. Clinical: BNO 3731 significantly alleviated symptoms of AD and improved physiological skin parameters. Itch intensity decreased significantly by 55%, and in 75% of subjects, itch improved ≥2 points on the NRS-11 scale. No adverse events were reported. BNO 3731, containing a unique synergistic combination of ginger extract and synthetic CBD, is an effective and safe treatment option for dry and eczema-prone skin, providing rapid and substantial relief of pruritus.

Asunto(s)

Antiinflamatorios , Cannabidiol , Dermatitis Atópica , Emulsiones , Extractos Vegetales , Zingiber officinale , Humanos , Cannabidiol/farmacología , Zingiber officinale/química , Dermatitis Atópica/tratamiento farmacológico , Extractos Vegetales/farmacología , Adulto , Femenino , Antiinflamatorios/farmacología , Masculino , Niño , Prurito/tratamiento farmacológico , Adolescente , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Antioxidantes/farmacología , Adulto Joven , Células Cultivadas

RESUMEN

BACKGROUND: Failure of treatment with gemcitabine in most cholangiocarcinoma (CCA) patients is due to drug resistance. The therapeutic potential of natural plant secondary compounds with minimal toxicity, such as cannabidiol (CBD), is a promising line of investigation in gemcitabine-resistant CCA. We aim to investigate the effects of CBD on gemcitabine-resistant CCA (KKU-213BGemR) cells in vitro and in vivo. MATERIALS: In vitro, cell proliferation, colony formation, apoptosis and cell cycle arrest were assessed using MTT assay, clonogenicity assay and flow cytometry. The effect of CBD on ROS production was evaluated using the DCFH-DA fluorescent probe. The mechanism exerted by CBD on ER stress-associated apoptosis was investigated by western blot analysis. A gemcitabine-resistant CCA xenograft model was also used and the expression of PCNA and CHOP were evaluated by immunohistochemical analysis. RESULTS: The IC50 values of CBD for KKU-213BGemR cells ranged from 19.66 to 21.05 µM. For a non-cancerous immortalized fibroblast cell line, relevant values were 18.29 to 19.21 µM. CBD suppressed colony formation by KKU-213BGemR cells in a dose-dependent manner in the range of 10 to 30 µM. CBD at 30 µM significantly increased apoptosis at early (16.37%) (P = 0.0024) and late (1.8%) stages (P < 0.0001), for a total of 18.17% apoptosis (P = 0.0017), in part by increasing ROS production (P < 0.0001). Multiphase cell cycle arrest significantly increased at G0/G1 with CBD 10 and 20 µM (P = 0.004 and P = 0.017), and at G2/M with CBD 30 µM (P = 0.005). CBD treatment resulted in increased expression of ER stress-associated apoptosis proteins, including p-PERK, BiP, ATF4, CHOP, BAX, and cytochrome c. In xenografted mouse, CBD significantly suppressed tumors at 10 and 40 mg/kg·Bw (P = 0.0007 and P = 0.0278, respectively), which was supported by an increase in CHOP, but a decrease in PCNA expression in tumor tissues (P < 0.0001). CONCLUSION: The results suggest that CBD exhibits potent anti-cancer activity against gemcitabine-resistant CCA in vitro and in vivo, in part via ER stress-mediated mechanisms. These results indicate that clinical explorative use of CBD on gemcitabine-resistant CCA patients is warranted.

Asunto(s)

Apoptosis , Cannabidiol , Colangiocarcinoma , Desoxicitidina , Resistencia a Antineoplásicos , Estrés del Retículo Endoplásmico , Gemcitabina , Colangiocarcinoma/tratamiento farmacológico , Cannabidiol/farmacología , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Animales , Humanos , Ratones , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Ratones Desnudos , Ratones Endogámicos BALB C , Antineoplásicos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

BACKGROUND: Chronic Gulf War Illness (GWI) is characterized by cognitive and mood impairments, as well as persistent neuroinflammation and oxidative stress. This study aimed to investigate the efficacy of Epidiolex®, a Food and Drug Administration (FDA)-approved cannabidiol (CBD), in improving brain function in a rat model of chronic GWI. METHODS: Six months after exposure to low doses of GWI-related chemicals [pyridostigmine bromide, N,N-diethyl-meta-toluamide (DEET), and permethrin (PER)] along with moderate stress, rats with chronic GWI were administered either vehicle (VEH) or CBD (20 mg/kg, oral) for 16 weeks. Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory, object location memory, pattern separation, and sucrose preference. The effect of CBD on hyperalgesia was also examined. The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests. RESULTS: GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia, whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia. Additionally, CBD treatment alleviated hyperalgesia in GWI rats. Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription (JAK/STAT) signaling. Furthermore, there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis. In contrast, the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling, normalized concentrations of proinflammatory cytokines and oxidative stress markers, and improved neurogenesis. Notably, CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus. CONCLUSIONS: The use of an FDA-approved CBD (Epidiolex®) has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI. Importantly, the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.

Asunto(s)

Cannabidiol , Disfunción Cognitiva , Hiperalgesia , Neurogénesis , Enfermedades Neuroinflamatorias , Síndrome del Golfo Pérsico , Animales , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Ratas , Síndrome del Golfo Pérsico/tratamiento farmacológico , Síndrome del Golfo Pérsico/complicaciones , Masculino , Hiperalgesia/tratamiento farmacológico , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Neurogénesis/efectos de los fármacos , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Trastornos del Humor/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Bromuro de Piridostigmina/farmacología , Bromuro de Piridostigmina/uso terapéutico

RESUMEN

Dental pulp stem cells (DPSC) have shown osteogenic and bone regenerative potential. Improving the in situ bone regeneration potential of DPSC is crucial for their application as seed cells during bone defect reconstruction in clinics. This study aimed to develop DPSC-derived organoid-like microspheroids as effective seeds for bone tissue engineering applications. DPSC osteogenic microspheroids (70 µm diameter) were cultured in a polydimethylsiloxane-mold-based agarose-gel microwell-culture-system with or without cannabidiol (CBD)-treatment. Results of in vitro studies showed higher osteogenic differentiation potential of microspheroids compared with 2D-cultured-DPSC. CBD treatment further improved the osteogenic differentiation potential of microspheroids. The effect of CBD treatment in the osteogenic differentiation of microspheroids was more pronounced compared with that of CBD-treated 2D-cultured-DPSC. Microspheroids showed a higher degree of bone regeneration in nude mice calvarial bone defect compared to 2D-cultured-DPSC. CBD-treated microspheroids showed the most robust in situ bone regenerative potential compared with microspheroids or CBD-treated 2D-cultured-DPSC. According to mRNA sequencing, bioinformatic analysis, and confirmation study, the higher osteogenic potential of CBD-treated microspheroids was mainly attributed to WNT6 upregulation. Taken together, DPSC microspheroids have robust osteogenic potential and can effectively translate the effect of in vitro osteoinductive stimulation during in situ bone regeneration, indicating their application potential during bone defect reconstruction in clinics.

Asunto(s)

Cannabidiol , Diferenciación Celular , Pulpa Dental , Osteogénesis , Células Madre , Regulación hacia Arriba , Osteogénesis/efectos de los fármacos , Animales , Cannabidiol/farmacología , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Células Madre/citología , Ratones , Regulación hacia Arriba/efectos de los fármacos , Pulpa Dental/citología , Pulpa Dental/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Organoides/efectos de los fármacos , Organoides/metabolismo , Humanos , Ratones Desnudos , Células Cultivadas , Regeneración Ósea/efectos de los fármacos

RESUMEN

Neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce psycho-motor malfunctions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-ß, huntingtin, and tau, and accumulation of the associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation. Cannabidiol (CBD) is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo. CBD has gained attention as a promising drug candidate for the management of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as the clinical applications of CBD in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.

Asunto(s)

Cannabidiol , Enfermedades Neurodegenerativas , Humanos , Cannabidiol/uso terapéutico , Cannabidiol/farmacología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Animales , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos