RESUMO

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.

Assuntos

RESUMO

HIV-associated neurocognitive disorders (HAND) affect 15-55% of HIV-positive patients and effective therapies are unavailable. HIV-infected monocyte-derived macrophages (MDM) invade the brain of these individuals, promoting neurotoxicity. We demonstrated an increased expression of cathepsin B (CATB), a lysosomal protease, in monocytes and post-mortem brain tissues of women with HAND. Increased CATB release from HIV-infected MDM leads to neurotoxicity, and their secretion is associated with NF-κB activation, oxidative stress, and lysosomal exocytosis. Cannabinoid receptor 2 (CB2R) agonist, JWH-133, decreases HIV-1 replication, CATB secretion, and neurotoxicity from HIV-infected MDM, but the mechanisms are not entirely understood. We hypothesized that HIV-1 infection upregulates the expression of proteins associated with oxidative stress and that a CB2R agonist could reverse these effects. MDM were isolated from healthy women donors (n = 3), infected with HIV-1ADA, and treated with JWH-133. After 13 days post-infection, cell lysates were labeled by Tandem Mass Tag (TMT) and analyzed by LC/MS/MS quantitative proteomics bioinformatics. While HIV-1 infection upregulated CATB, NF-κB signaling, Nrf2-mediated oxidative stress response, and lysosomal exocytosis, JWH-133 treatment downregulated the expression of the proteins involved in these pathways. Our results suggest that JWH-133 is a potential alternative therapy against HIV-induced neurotoxicity and warrant in vivo studies to test its potential against HAND.

Assuntos

RESUMO

Determining peripheral modulation of the endocannabinoid system (ECS) may be important for differentiating individuals with schizophrenia. Such differentiation can also be extended to subgroups of individuals, those who use cannabis and antipsychotic medications, particularly those who are treatment resistant. Patients and controls were recruited from the outpatient clinic of the Psychosis Group of the University of São Paulo, Brazil. A final sample of 93 individuals was divided into 3 groups: patients with schizophrenia using clozapine (treatment-resistant) (n = 29), patients with schizophrenia using another antipsychotic (n = 31), and controls (n = 33). By measuring the proteins and metabolites involved in the ECS pathways in the peripheral blood, AEA (anandamide), 2-AG (2-arachidonoyl ethanolamine), and CB2 receptor (peripheral) were quantified. Individuals reporting lifetime cannabis use had lower 2-AG plasma levels (p = 0.011). Regarding the CB2 receptor, the values of patients with schizophrenia and controls were similar, but those of patients using antipsychotics other than clozapine differed (p = 0.022). In generalized linear models to control for confounders, the use of cannabis remained the only factor that significantly influenced 2-AG levels. The relationship for non-clozapine antipsychotics as the only factor related to CB2 changes was marginally significant. We found for the first time that cannabis use and non-clozapine antipsychotic medication are potentially involved in the modulation of the ECS, specifically influencing 2-AG endocannabinoid and CB2 receptor levels. More studies regarding the ECS are needed since it has been increasingly related to the physiopathology of schizophrenia.

RESUMO

Graft-versus-host disease (GVHD) is a serious inflammatory illness that often occurs as a secondary complication of bone marrow transplantation. Current therapies have limited effectiveness and fail to achieve a balance between inflammation and the graft-versus-tumor effect. In this study, we investigate the effects of the endocannabinoid anandamide on the complex pathology of GVHD. We assess the effects of an irreversible inhibitor of fatty acid amine hydrolase or exogenous anandamide and find that they increase survival and reduce clinical signs in GVHD mice. In the intestine of GVHD mice, treatment with exogenous anandamide also leads to a reduction in the number of CD3+, CD3+CD4+, and CD3+CD8+ cells, which reduces the activation of CD3+CD4+ and CD3+CD8+ cells, as assessed by enhanced CD28 expression, a T cell co-stimulatory molecule. Exogenous AEA was also able to reduce TNF-α and increase IL-10 in the intestine of GVHD mice. In the liver, exogenous AEA reduces injury, TNF-α levels, and the number of CD3+CD8+ cells. Interestingly, anandamide reduces Mac-1α, which lowers the adhesion of transplanted cells in mesenteric veins. These effects are mimicked by JWH133-a CB2 selective agonist-and abolished by treatment with a CB2 antagonist. Furthermore, the effects caused by anandamide treatment on survival were related to the CB2 receptor, as the CB2 antagonist abolished it. This study shows the critical role of the CB2 receptor in the modulation of the inflammatory response of GVHD by treatment with anandamide, the most prominent endocannabinoid.

Assuntos

RESUMO

The endocannabinoid system (ECS) constitutes a broad-spectrum modulator of homeostasis in mammals, providing therapeutic opportunities for several pathologies. Its two main receptors, cannabinoid type 1 (CB1) and type 2 (CB2) receptors, mediate anti-inflammatory responses; however, their differing patterns of expression make the development of CB2-selective ligands therapeutically more attractive. The benzo[d]imidazole ring is considered to be a privileged scaffold in drug discovery and has demonstrated its versatility in the development of molecules with varied pharmacologic properties. On the other hand, the main psychoactive component of Cannabis sativa, delta-9-tetrahydrocannabinol (THC), can be structurally described as an aliphatic terpenoid motif fused to an aromatic polyphenolic (resorcinol) structure. Inspired by the structure of this phytocannabinoid, we combined different natural product motifs with a benzo[d]imidazole scaffold to obtain a new library of compounds targeting the CB2 receptor. Here, we synthesized 26 new compounds, out of which 15 presented CB2 binding and 3 showed potent agonist activity. SAR analysis indicated that the presence of bulky aliphatic or aromatic natural product motifs at position 2 of the benzo[d]imidazoles ring linked by an electronegative atom is essential for receptor recognition, while substituents with moderate bulkiness at position 1 of the heterocyclic core also participate in receptor recognition. Compounds 5, 6, and 16 were further characterized through in vitro cAMP functional assay, showing potent EC50 values between 20 and 3 nM, and compound 6 presented a significant difference between the EC50 of pharmacologic activity (3.36 nM) and IC50 of toxicity (30-38 µM).

Assuntos

RESUMO

Mast cells (MCs) are the main participants in the control of immune reactions associated with inflammation, allergies, defense against pathogens, and tumor growth. Bioactive lipids are lipophilic compounds able to modulate MC activation. Here, we explored some of the effects of the bioactive lipid lysophosphatidylinositol (LPI) on MCs. Utilizing murine bone marrow-derived mast cells (BMMCs), we found that LPI did not cause degranulation, but slightly increased FcεRI-dependent ß-hexosaminidase release. However, LPI induced strong chemotaxis together with changes in LIM kinase (LIMK) and cofilin phosphorylation. LPI also promoted modifications to actin cytoskeleton dynamics that were detected by an increase in cell size and interruptions in the continuity of the cortical actin ring. The chemotaxis and cortical actin ring changes were dependent on GPR55 receptor activation, since the specific agonist O1602 mimicked the effects of LPI and the selective antagonist ML193 prevented them. The LPI and O1602-dependent stimulation of BMMC also led to VEGF, TNF, IL-1α, and IL-1ß mRNA accumulation, but, in contrast with chemotaxis-related processes, the effects on cytokine transcription were dependent on GPR55 and cannabinoid (CB) 2 receptors, since they were sensitive to ML193 and to the specific CB2 receptor antagonist AM630. Remarkably, GPR55-dependent BMMC chemotaxis was observed towards conditioned media from distinct mouse and human cancer cells. Our data suggest that LPI induces the chemotaxis of MCs and leads to cytokine production in MC in vitro with the differential participation of GPR55 and CB2 receptors. These effects could play a significant role in the recruitment of MCs to tumors and the production of MC-derived pro-angiogenic factors in the tumor microenvironment.

Assuntos

RESUMO

INTRODUCTION: The use of the Cannabis sativa plant by man has been common for centuries due to its numerous therapeutic properties resulting from the compounds present in it, called cannabinoids. However, the use of these compounds as drugs is still limited due to the psychotropic effects caused by them. The proteins that act as receptors of cannabinoid compounds were identified and characterized, being called CB1 and CB2 receptors. There is a series of 50 cannabinoid compounds that was studied through quantum and chemometric methods in order to obtain a mathematical model that could relate the structure of these compounds to their psychotropic activity. That model proved to be effective by predicting the psychoactivity of the 50 compounds from the series and elucidating relevant characteristics that imply in psychoactivity. However, most of these 50 compounds do not have experimental data of biological activity with CB1 and CB2 receptors. OBJECTIVES: This study aims to generate QSAR models in order to predict the biological activity of the 50 cannabinoid compounds and then relate the predicted biological activity values to the already known psychoactivity. METHODS: Another series of cannabinoid compounds was selected to generate and validate QSAR models, aiming to predict the biological activity of the 50 cannabinoid compounds with both CB1 and CB2 receptors. RESULTS: The PLS-CB1 and PLS-CB2 QSAR models were generated and validated in this work, proving to be highly predictive, and the biological activities (pK ) of the 50 cannabinoid compounds were predicted by them. It is important to highlight compounds Ic14, Ic18, and Ic19 (psychotropic inactive) which presented higher predicted pK values than the main cannabinoid compounds (Δ9-THC and Δ8-THC). Also, compound Ic21 stood out as the highest value of the predicted biological activities in the interaction with the CB2 receptor. CONCLUSION: The generated PLS models and the predicted pKi values of the 50 cannabinoid compounds can provide valuable information in the drug design of new cannabinoid compounds that can interact with CB1 and CB2 receptors in a therapeutic way with no psychotropic effects.

Assuntos

RESUMO

BACKGROUND AND PURPOSE: Cannabis legalization has risen in many countries, and its use during pregnancy has increased. The endocannabinoid system is present in the CNS at early stages of embryonic development, and regulates functional brain maturation including areas responsible for respiratory control, data on the influence of external cannabinoids on the development of the respiratory system and possible consequences during postnatal life are limited. EXPERIMENTAL APPROACH: We evaluated the effects of prenatal exposure to synthetic cannabinoid (WIN 55,212-2 [WIN], 0.5 mg·kg-1 ·day-1 ) on the respiratory control system in neonatal (P0, P6-7 and P12-13) and juvenile (P27-28) male and female rats. KEY RESULTS: WIN administration to pregnant rats interfered sex-specifically with breathing regulation of offspring, promoting a greater sensitivity to CO2 at all ages in males (except P6-7) and in juvenile females. An altered hypoxic chemoreflex was observed in P0 (hyperventilation) and P6-7 (hypoventilation) males, which was absent in females. Along with breathing alterations, brainstem analysis showed an increase in the number of catecholaminergic neurons and cannabinoid receptor type 1 (CB1 ) and changes in tissue respiration in the early males. A reduction in pulmonary compliance was observed in juvenile male rats. Preexposure to WIN enhanced spontaneous apnoea and reduced the number of serotoninergic (5-HT) neurons in the raphe magnus nucleus of P0 females. CONCLUSIONS AND IMPLICATIONS: These data demonstrate that excess stimulation of the endocannabinoid system during gestation has prolonged and sex-specific consequences for the respiratory control system.

Assuntos

RESUMO

ß-caryophyllene (BCP) is a cannabinoid receptor CB2 agonist plant-derived terpenoid found in different essential oil plants, including rosemary, black pepper, copaiba and cannabis. It has GRAS (generally recognized as safe) status and is approved by the FDA (Food and Drug Administration) for food use. BCP displays agonist activity on the CB2 receptor and is a potential therapeutic target in several neuropsychiatric disorders, including anxiety and drug addiction. Unlike CB1 receptors, activation of the CB2 receptors is devoid of psychotomimetic and addictive properties. In this regard, this study aimed to evaluate the effects of BCP on incentive salience ("wanting") performance and motivational properties elicited by sweetened palatable foods in female Swiss mice. After 9 days of training for incentive salience performance for a sweet reward (hazelnut cream with chocolate), food-restricted mice received a systemic injection of BCP (50 and 100 mg/kg) before testing over 3 days. Moreover, independent groups of female mice were tested on sweet reward-induced conditioned place preference (CPP) for 22 consecutive days. To evaluate BCP effects on the expression of seeking behaviour for sweetened food, mice received a single intraperitoneal injection of BCP (50 mg/kg) 30 min before testing on the CPP task. BCP significantly decreased the incentive performance for a sweet reward compared with the control group in a CB2 receptor-dependent manner. Also, BCP suppressed the expression of sweet reward-CPP. Altogether, these preclinical data demonstrate the potential role of BCP in treating disorders associated with food addiction-like behaviour.

Assuntos

RESUMO

Introdução: A periodontite é um importante problema de saúde pública. Embora o princípio da terapia da periodontite esteja focado principalmente na remoção do biofilme dental e dos fatores associados, sua fisiopatologia registra diferentes eventos moleculares e inflamatórios relacionados ao sistema imunológico do hospedeiro, como a participação do sistema endocanabinoide. Objetivo: Esta revisão teve como objetivo explorar e elucidar os mecanismos e papéis do sistema endocanabinoide na fisiopatologia da periodontite e suas possibilidades para futuras terapias relacionadas. Material e método: Realizou-se uma busca eletrônica na plataforma PubMed por estudos envolvendo a ação do sistema endocanabinoide sobre a periodontite. Resultado: Dezenove estudos clínicos e pré-clínicos foram incluídos nesta revisão narrativa. Conclusão: Os receptores canabinoides tipo 1 e 2 são componentes integrais do sistema endocanabinoide e manifestam-se de várias formas nos tecidos periodontais. As ações e mecanismos através dos quais os receptores canabinoides são ativados em locais saudáveis ou inflamados continuam a ser o foco de investigações em curso. Além disso, os fitocanabinoides e canabinoides sintéticos apresentam potencial como tratamentos, com estudos pré-clínicos indicando benefícios na redução da inflamação e na facilitação da reparação dos tecidos.

Introduction: Periodontitis is a major public health problem. Although the principle of periodontitis therapy is mainly focused on removing dental biofilm and associated factors, its physiopathology enrolls different molecular and inflammatory events related to the host immune system, as the participation of the endocannabinoid system. Objective: This review aimed to explore and elucidate the mechanisms and roles of the endocannabinoid system on periodontitis physiopathology and its possibilities for future related therapies. Material and method: An electronic search was carried out on the PubMed platform for studies involving the action of the endocannabinoid system on periodontitis. Result: Nineteen clinical and preclinical studies were included in this narrative review. Conclusion: Cannabinoid receptors type 1 and 2 are integral components of the endocannabinoid system, manifesting in various forms in the periodontal tissues. The actions and mechanisms through which cannabinoid receptors are activated in healthy or inflamed sites remain the focus of ongoing investigations. Moreover, phytocannabinoids and synthetic cannabinoids show therapeutic potential, with pre-clinical studies indicating benefits in reducing inflammation and facilitating tissue repair

Assuntos

RESUMO

ABSTRACT Objective To verify the involvement of the endocannabinoid system in the immunomodulatory profile of stem cells from human exfoliated deciduous teeth, in the presence or absence of TNF-α, and agonist and antagonists of CB1 and CB2. Methods Stem cells from human exfoliated deciduous teeth were cultured in the presence or absence of an agonist, anandamide, and two antagonists, AM251 and SR144528, of CB1 and CB2 receptors, with or without TNF-α stimulation. For analysis of immunomodulation, surface molecules linked to immunomodulation, namely human leukocyte antigen-DR isotype (HLA-DR), and programmed death ligands 1 (PD-L1) and 2 (PD-L2) were measured using flow cytometry. Results The inhibition of endocannabinoid receptors together with the proinflammatory effect of TNF-α resulted in increased HLA-DR expression in stem cells from human exfoliated deciduous teeth, as well as, in these cells acquiring an anti-inflammatory profile by enhancing the expression of PD-L1 and PD-L2. Conclusion Stem cells from human exfoliated deciduous teeth respond to the endocannabinoid system and TNF-α by altering key immune response molecules.

RESUMO

Among the most recent proposals regarding the mechanism of action of dipyrone, the modulation of cannabinoid receptors CB1 and CB2 appears to be a promising hypothesis. In this context, the present work describes a series of five novel pyrazolamides (7-11) designed as molecular hybrids of dipyrone metabolites and NSAIDs, such as ibuprofen and flurbiprofen. Target compounds were obtained in good overall yields (50-80%) by classical amide coupling between 4-aminoantipyrine and arylacetic or arylpropionic acids, followed in some cases by N-methylation of the amide group. The compounds presented good physicochemical properties in addition to stability to chemical (pH 2 and 7.4) and enzymatic (plasma esterases) hydrolysis and showed medium to high gastrointestinal and BBB permeabilities in the PAMPA assay. When subjected to functional testing on CB1- or CB2-transfected cells, compounds demonstrated an inverse agonist profile on CB2 receptors and the further characterization of compound LASSBio-2265 (11) revealed moderate binding affinity to CB2 receptor (Ki = 16 µM) with an EC50 = 0.36 µM (Emax = 63%). LASSBio-2265 (11) (at 1, 3, and 10 mg/kg p.o.) was investigated in the formalin test in mice and a remarkable analgesic activity in the late inflammatory phase was observed, suggesting it could be promising for the treatment of pain syndromes associated with chronic inflammatory diseases.

RESUMO

Odontoblasts and gingival fibroblasts play essential roles in the physiological and pathological processes of dental tissue. Cannabinoid receptors (CB1 and CB2) are involved in analgesia by modulating the función of calcium channels that inhibit the synthesis of some neurotransmitters. A better understanding of the physiology of these receptors would provide the possibility of using them as therapeutic targets in controlling dental pain. The aim of this study was to evaluate the presence and activity of cannabinoid receptors in human odontoblast-like cells (OLC) and human gingival fibroblasts (HGF). CB1 and CB2 transcription was analyzed by real-time PCR, proteins were detected by immunofluorescence, and functional cannabinoid receptors were evaluated by measuring intracellular calcium concentration after stimulation with cannabidiol (CBD) and pre-treatment with a CB1 antagonist, a CB2 inverse agonist and a TRPV1 antagonist. Transcripts for CB1 and CB2 were found in both odontoblasts and gingival fibroblasts. Cannabidiol induced an increase in [Ca2+]i in both cells types, but surprisingly, pre-treatment with selective cannabinoid antagonists attenuated this effect, suggesting a functional communication between specific cannabinoid receptors and other CBD target receptors. In conclusion, human odontoblasts and gingival fibroblasts express functional CB1 and CB2 cannabinoid receptors, which could be modulated to improve the treatment of pain or dental sensitivity.

Los odontoblastos y los fibroblastos gingivales desempeñan funciones esenciales en los procesos fisiológicos y patológicos de los tejidos dentales. Los receptores cannabinoides (CB1 y CB2) participan en la analgesia mediante la modulación de la función de canales de calcio que inhiben la síntesis de algunos neurotransmisores. Un mejor conocimiento de su fisiología abre la posibilidad de utilizar estos receptores como dianas terapéuticas en el control del dolor dental. Este trabajo tuvo como objetivo evaluar la presencia y la actividad de los receptores cannabinoides en células humanas similares a los odontoblastos (OLC) y en fibroblastos gingivales humanos (HGF). Se analizó la transcripción de CB1 y CB2 por PCR en tiempo real, la detección de las proteínas por inmunofluorescencia y se evaluaron los receptores cannabinoides funcionales midiendo las concentraciones de calcio intracelular, tras la estimulación con cannabidiol (CBD) y el pretratamiento con un antagonista de CB1, un agonista inverso de CB2 y un antagonista de TRPV1. Se encontraron mensajeros para CB1 y CB2 tanto en odontoblastos como en fibroblastos gingivales. El cannabidiol indujo un aumento de la [Ca2+]i en ambos tipos de células, pero sorprendentemente el pretratamiento con antagonistas cannabinoides selectivos atenuó este efecto, lo que sugiere una comunicación funcional entre receptores cannabinoides específicos y otros receptores diana del CBD. En conclusión, los odontoblastos humanos y los fibroblastos gingivales expresan receptores cannabinoides CB1 y CB2 funcionales, que podrían ser modulados para mejorar el tratamiento del dolor o la sensibilidad dental.

Assuntos

RESUMO

ABSTRACT Odontoblasts and gingival fibroblasts play essential roles in the physiological and pathological processes of dental tissue. Cannabinoid receptors (CB1 and CB2) are involved in analgesia by modulating the función of calcium channels that inhibit the synthesis of some neurotransmitters. A better understanding of the physiology of these receptors would provide the possibility of using them as therapeutic targets in controlling dental pain. The aim of this study was to evaluate the presence and activity of cannabinoid receptors in human odontoblast-like cells (OLC) and human gingival fibroblasts (HGF). CB1 and CB2 transcription was analyzed by real-time PCR, proteins were detected by immunofluorescence, and functional cannabinoid receptors were evaluated by measuring intracellular calcium concentration after stimulation with cannabidiol (CBD) and pre-treatment with a CB1 antagonist, a CB2 inverse agonist and a TRPV1 antagonist. Transcripts for CB1 and CB2 were found in both odontoblasts and gingival fibroblasts. Cannabidiol induced an increase in [Ca2+]i in both cells types, but surprisingly, pre-treatment with selective cannabinoid antagonists attenuated this effect, suggesting a functional communication between specific cannabinoid receptors and other CBD target receptors. In conclusion, human odontoblasts and gingival fibroblasts express functional CB1 and CB2 cannabinoid receptors, which could be modulated to improve the treatment of pain or dental sensitivity.

RESUMEN Los odontoblastos y los fibroblastos gingivales desempeñan funciones esenciales en los procesos fisiológicos y patológicos de los tejidos dentales. Los receptores cannabinoides (CB1 y CB2) participan en la analgesia mediante la modulación de la función de canales de calcio que inhiben la síntesis de algunos neurotransmisores. Un mejor conocimiento de su fisiología abre la posibilidad de utilizar estos receptores como dianas terapéuticas en el control del dolor dental. Este trabajo tuvo como objetivo evaluar la presencia y la actividad de los receptores cannabinoides en células humanas similares a los odontoblastos (OLC) y en fibroblastos gingivales humanos (HGF). Se analizó la transcripción de CB1 y CB2 por PCR en tiempo real, la detección de las proteínas por inmunofluorescencia y se evaluaron los receptores cannabinoides funcionales midiendo las concentraciones de calcio intracelular, tras la estimulación con cannabidiol (CBD) y el pretratamiento con un antagonista de CB1, un agonista inverso de CB2 y un antagonista de TRPV1. Se encontraron mensajeros para CB1 y CB2 tanto en odontoblastos como en fibroblastos gingivales. El cannabidiol indujo un aumento de la [Ca2+]i en ambos tipos de células, pero sorprendentemente el pretratamiento con antagonistas cannabinoides selectivos atenuó este efecto, lo que sugiere una comunicación funcional entre receptores cannabinoides específicos y otros receptores diana del CBD. En conclusión, los odontoblastos humanos y los fibroblastos gingivales expresan receptores cannabinoides CB1 y CB2 funcionales, que podrían ser modulados para mejorar el tratamiento del dolor o la sensibilidad dental.

RESUMO

Addiction to psychostimulant drugs, such as cocaine, D-amphetamine, and methamphetamine, is a public health issue that substantially contributes to the global burden of disease. Psychostimulant drugs promote an increase in dopamine levels within the mesocorticolimbic system, which is central to the rewarding properties of such drugs. Cannabinoid receptors (CB1R and CB2R) are expressed in the main areas of this system and implicated in the neuronal mechanisms underlying the rewarding effect of psychostimulant drugs. Here, we reviewed studies focusing on pharmacological intervention targeting cannabinoid CB1R and CB2R and their interaction in the modulation of psychostimulant responses.

RESUMO

Cannabinoid signaling, mainly via CB1 and CB2 receptors, plays an essential role in oligodendrocyte health and functions. However, the specific molecular signals associated with the activation or blockade of CB1 and CB2 receptors in this glial cell have yet to be elucidated. Mass spectrometry-based shotgun proteomics and in silico biology tools were used to determine which signaling pathways and molecular mechanisms are triggered in a human oligodendrocytic cell line (MO3.13) by several pharmacological stimuli: the phytocannabinoid cannabidiol (CBD); CB1 and CB2 agonists ACEA, HU308, and WIN55, 212-2; CB1 and CB2 antagonists AM251 and AM630; and endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The modulation of cannabinoid signaling in MO3.13 was found to affect pathways linked to cell proliferation, migration, and differentiation of oligodendrocyte progenitor cells. Additionally, we found that carbohydrate and lipid metabolism, as well as mitochondrial function, were modulated by these compounds. Comparing the proteome changes and upstream regulators among treatments, the highest overlap was between the CB1 and CB2 antagonists, followed by overlaps between AEA and 2-AG. Our study opens new windows of opportunities, suggesting that cannabinoid signaling in oligodendrocytes might be relevant in the context of demyelinating and neurodegenerative diseases. Proteomics data are available at ProteomeXchange (PXD031923).

Assuntos

RESUMO

Low-grade inflammation of the hypothalamus is associated with the disturbance of energy balance. The endocannabinoid system has been implicated in the development and maintenance of obesity as well as in the control of immune responses. The type 2 cannabinoid receptor (CB2) signaling has been associated with anti-inflammatory effects. Therefore, in high fat diet (HFD)-induced obese mice, we modulated CB2 signaling and investigated its effects on energy homeostasis and hypothalamic microgliosis/astrogliosis. We observed no effect on caloric intake and body weight gain in control diet-fed animals that received prolonged icv infusion of the CB2 receptor agonist HU308. Interestingly, we observed a decrease in glucose tolerance in HFD-fed animals treated with HU308. Prolonged icv infusion of HU308 increases astrogliosis in the ventromedial nucleus (VMH) of obese animals and reduced HFD-induced microgliosis in the hypothalamic arcuate (ARC) but not in the paraventricular (PVN) or VMH nuclei. These data indicate that central CB2 signaling modulates glucose homeostasis and glial reactivity in obesogenic conditions, irrespective of changes in body weight.

Assuntos

RESUMO

The global pandemic caused by the SARS-CoV-2 virus began in early 2020 and is still present. The respiratory symptoms caused by COVID-19 are well established. However, neurological manifestations that may result from direct or indirect neurological damage after SARS-CoV-2 infection have been reported frequently. The main proposed pathophysiological processes leading to neurological damage in COVID-19 are cerebrovascular disease and indirect inflammatory/ autoimmune origin mechanisms. A growing number of studies confirm that neuroprotective measures should be maintained in COVID-19 patients. On the other hand, cannabinoids have been the subject of various studies that propose them as potentially promising drugs in chronic neurodegenerative diseases due to their powerful neuroprotective potential. In this review, we addresses the possible mechanism of action of cannabinoids as a neuroprotective treatment in patients infected by SARS-CoV-2. The endocannabinoid system is found in multiple systems within the body, including the immune system. Its activation can lead to beneficial results, such as a decrease in viral entry, a reduction of viral replication, and a reduction of pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-12, TNF-α, or IFN-c through CB2R expression induced during inflammation by SARS-CoV-2 infection in the central nervous system.

Assuntos

RESUMO

Zebrafish is considered an unprecedented animal model in drug discovery. A review of the literature presents highlights and elucidates the biological effects of chemical components found in Cannabis sativa. Particular attention is paid to endocannabinoid system (eCB) and its main receptors (CB1 and CB2). The zebrafish model is a promising one for the study of cannabinoids because of the many similarities to the human system. Despite the recent advances on the eCB system, there is still the need to elucidate some of the interactions and, thus, the zebrafish model can be used for that purpose as it respects the 3Rs concept and reduced time and costs. In view of the relevance of cannabinoids in the treatment and prevention of diseases, as well as the importance of the zebrafish animal model in elucidating the biological effects of new drugs, the aim of this study was to bring to light information on the use of the zebrafish animal model in testing C. sativa-based medicines.

RESUMO

Epilepsy is a neurological disorder with a high prevalence worldwide. Several studies carried out during the last decades indicate that the administration of cannabinoids as well as the activation of the endocannabinoid system (ECS) represent a therapeutic strategy to control epilepsy. However, there are controversial studies indicating that activation of ECS results in cell damage, inflammation and neurotoxicity, conditions that facilitate the seizure activity. The present review is focused to present findings supporting this issue. According to the current discrepancies, it is relevant to elucidate the different effects induced by the activation of ECS and determine the conditions under which it facilitates the seizure activity.

Assuntos