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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.
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Background: Sex differences in the response to the anxiety-related effects of cannabinoid drugs have been reported, with females being more sensitive than males. Evidence suggests that, according to sex and estrous cycle phase (ECP), the content of the endocannabinoids (eCBs) N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) varies in brain areas involved in the anxiety-like behavior. Methods: Considering the lack of studies evaluating sex and ECP differences in the eCB system in anxiety, using URB597, a fatty acid amide hydrolase inhibitor, or MJN110, a monoacylglycerol lipase inhibitor, we explored the effects of increasing AEA or 2-AG levels, respectively, in cycling and ovariectomized (OVX) female adult Wistar rats, as well as males, subjected to the elevated plus maze. Results: The administration of URB597 (0.1 or 0.3mg/kg; intraperitoneally) either increased or reduced the percentage of open arms time (%OAT) and open arms entries (%OAE), being anxiolytic in diestrus and anxiogenic in estrus. No effects were observed in proestrus or when all ECPs were analyzed together. Both doses produced anxiolytic-like effects in males. In OVX females, the anxiolytic-like effect of URB597 0.1 was associated with low levels of estradiol, whereas the anxiogenic-like effect of URB597 0.3 was spared by estradiol pretreatment. The systemic administration of MJN110 3.0 mg/kg reduced the risk assessment behavior (RAB), suggesting an anxiolytic-like effect independent of the ECP. When considering the ECP, MJN110 3.0 increased the %OAT and reduced the RAB, being anxiolytic in estrus and diestrus. No effects were observed in proestrus. Both doses of MJN110 were anxiogenic in males. In OVX females, the anxiolytic-like effect of MJN110 was dependent on low estradiol levels. Conclusion: Together, our findings support the evidence that females react differently to the effects of cannabinoids in the anxiety-like behavior; in addition, AEA and 2-AG modulation elicits anxiety-like responses that are closely influenced by hormone levels, mainly estradiol.
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The onset of frank psychosis is usually preceded by a prodromal phase characterized by attenuated psychotic symptoms. Currently, research on schizophrenia prodromal phase (ultra-high risk for psychosis [UHR]) has focused on the risk of developing psychosis, on the transition to full blown psychosis and on its prediction. Neurobiological differences between UHR individuals who fully recover (remitters) versus those who show persistent/progressive prodromal symptoms (nonremitters) have been little explored. The endocannabinoid system constitutes a neuromodulatory system that plays a major role in brain development, synaptic plasticity, emotional behaviours and cognition. It comprises two cannabinoid receptors (CB1/CB2), two endocannabinoid ligands, arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2AG) along with their inactivation enzymes. Despite much evidence that the endocannabinoid system is imbalanced during psychosis, very little is known about it in UHR. Therefore, we aimed to quantify the plasma endocannabinoid levels in UHR and healthy controls (HC) and verify if these metabolites could differentiate between remitters and nonremitters. Circulating concentrations of AEA (p = .003) and 2AG (p < .001) were lower in UHR when compared with HC, with no difference between remitters and nonremitters. Regarding clinical evolution, it was observed that out of 91 UHRs initially considered, 16 had psychiatric complaints (3 years of follow-up). Considering those subjects, there were weak correlations between clinical parameters and plasma concentrations of endocannabinoids. Our results suggest that the endocannabinoids are imbalanced before frank psychosis and that changes can be seen in plasma of UHR individuals. These molecules proved to be potential biomarkers to identify individuals in the prodromal phase of psychosis.
Assuntos
Transtornos Psicóticos , Esquizofrenia , Endocanabinoides , Humanos , Sintomas Prodrômicos , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/psicologia , Fatores de Risco , Esquizofrenia/diagnósticoRESUMO
COVID-19, as the cause of a global pandemic, has resulted in lockdowns all over the world since early 2020. Both theoretical and experimental efforts are being made to find an effective treatment to suppress the virus, constituting the forefront of current global safety concerns and a significant burden on global economies. The development of innovative materials able to prevent the transmission, spread, and entry of COVID-19 pathogens into the human body is currently in the spotlight. The synthesis of these materials is, therefore, gaining momentum, as methods providing nontoxic and environmentally friendly procedures are in high demand. Here, a highly virucidal material constructed from SiO2-Ag composite immobilized in a polymeric matrix (ethyl vinyl acetate) is presented. The experimental results indicated that the as-fabricated samples exhibited high antibacterial activity towards Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) as well as towards SARS-CoV-2. Based on the present results and radical scavenger experiments, we propose a possible mechanism to explain the enhancement of the biocidal activity. In the presence of O2 and H2O, the plasmon-assisted surface mechanism is the major reaction channel generating reactive oxygen species (ROS). We believe that the present strategy based on the plasmonic effect would be a significant contribution to the design and preparation of efficient biocidal materials. This fundamental research is a precedent for the design and application of adequate technology to the next-generation of antiviral surfaces to combat SARS-CoV-2.
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The endocannabinoid 2-arachidonoylglycerol (2-AG) is an atypical neurotransmitter synthesized on demand in response to a wide range of stimuli, including exposure to stress. Through the activation of cannabinoid receptors, 2-AG can interfere with excitatory and inhibitory neurotransmission in different brain regions and modulate behavioural, endocrine and emotional components of the stress response. Exposure to chronic or intense unpredictable stress predisposes to maladaptive behaviour and is one of the main risk factors involved in developing mood disorders, such as major depressive disorder (MDD). In this review, we describe the molecular mechanisms involved in 2-AG signalling in the brain of healthy and stressed animals and discuss how such mechanisms could modulate stress adaptation and susceptibility to depression. Furthermore, we review preclinical evidence indicating that the pharmacological modulation of 2-AG signalling stands as a potential new therapeutic target in treating MDD. Particular emphasis is given to the pharmacological augmentation of 2-AG levels by monoacylglycerol lipase (MAGL) inhibitors and the modulation of CB2 receptors.
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Antidepressivos/farmacologia , Ácidos Araquidônicos/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Animais , Antidepressivos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/patologia , Transtorno Depressivo Maior/psicologia , Modelos Animais de Doenças , Humanos , Monoacilglicerol Lipases/antagonistas & inibidores , Monoacilglicerol Lipases/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Transmissão Sináptica/efeitos dos fármacosRESUMO
Biliary lithiasis is a multifactorial pathology determined by the interaction of genes and the environment, characterized by alterations in cholesterol homeostasis and in the metabolism of bile salts. A number of gene polymorphisms and mutations have been identified in the ATP-dependent cholesterol transporter (ABCG8) associated with lithiasis disease. The aim of the present study was to evaluate the association of the ABCG8 gene mutation IVS1-2A>G with cholecystolithiasis in patients from Northeast Mexico. This was a pilot study including 90 Mexican subjects diagnosed by ultrasonography, 57.8% of which presented gallstones. The studied parameters included: Lipid profile, total protein in plasma and polymerase chain reaction-restriction fragment length polymorphism genotyping. Significant differences were identified in total plasma protein, weight and BMI values, with these being these higher in subjects with gallstones (P<0.05). The presence of the mutant allele IVS1-2G was not detected, and the IVS1-2A wild-type allele was present in 100% of the population. Therefore, no association was apparent between the presence of the splice site mutation in ABCG8 (IVS1-2A>G) and the presence of gallstones in the evaluated subjects.
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A four stage semi-pilot scale RFR reactor with ceramic disks as support for TiO2 modified with silver particles was developed for the removal of organic pollutants. The design presented in this article is an adaptation of the rotating biological reactors (RBR) and its coupling with the modified catalyst provides additional advantages to designs where a catalyst in suspension is used. The optimal parameter of rotation was 54 rpm and the submerged surface of the disks offer a total contact area of 387 M². The modified solid showed a decrease in the value of its bandgap compared to commercial titanium. The system has a semi-automatic operation with a maximum reaction time of 50 h. Photo-activity tests show high conversion rates at low concentrations. The results conform to the Langmuir heterogeneous catalysis model.
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Prata/química , Titânio/química , Purificação da Água/instrumentação , Catálise , Cinética , Luz , Oxirredução , Processos Fotoquímicos , Propriedades de Superfície , Termodinâmica , Eliminação de Resíduos Líquidos/instrumentaçãoRESUMO
Polyunsaturated fatty acids (PUFAs) are lipid derivatives of omega-3 (docosahexaenoic acid, DHA, and eicosapentaenoic acid, EPA) or of omega-6 (arachidonic acid, ARA) synthesized from membrane phospholipids and used as a precursor for endocannabinoids (ECs). They mediate significant effects in the fine-tune adjustment of body homeostasis. Phyto- and synthetic cannabinoids also rule the daily life of billions worldwide, as they are involved in obesity, depression and drug addiction. Consequently, there is growing interest to reveal novel active compounds in this field. Cloning of cannabinoid receptors in the 90s and the identification of the endogenous mediators arachidonylethanolamide (anandamide, AEA) and 2-arachidonyglycerol (2-AG), led to the characterization of the endocannabinoid system (ECS), together with their metabolizing enzymes and membrane transporters. Today, the ECS is known to be involved in diverse functions such as appetite control, food intake, energy balance, neuroprotection, neurodegenerative diseases, stroke, mood disorders, emesis, modulation of pain, inflammatory responses, as well as in cancer therapy. Western diet as well as restriction of micronutrients and fatty acids, such as DHA, could be related to altered production of pro-inflammatory mediators (e.g. eicosanoids) and ECs, contributing to the progression of cardiovascular diseases, diabetes, obesity, depression or impairing conditions, such as Alzheimer' s disease. Here we review how diets based in PUFAs might be linked to ECS and to the maintenance of central and peripheral metabolism, brain plasticity, memory and learning, blood flow, and genesis of neural cells.
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Endocanabinoides/farmacologia , Ácidos Graxos Insaturados/farmacologia , Envelhecimento/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológicoRESUMO
Perinatal maternal high-fat (HF) diet programmes offspring obesity. Obesity is associated with overactivation of the endocannabinoid system (ECS) in adult subjects, but the role of the ECS in the developmental origins of obesity is mostly unknown. The ECS consists of endocannabinoids, cannabinoid receptors (cannabinoid type-1 receptor (CB1) and cannabinoid type-2 receptor (CB2)) and metabolising enzymes. We hypothesised that perinatal maternal HF diet would alter the ECS in a sex-dependent manner in white and brown adipose tissue of rat offspring at weaning in parallel to obesity development. Female rats received standard diet (9 % energy content from fat) or HF diet (29 % energy content from fat) before mating, during pregnancy and lactation. At weaning, male and female offspring were killed for tissue harvest. Maternal HF diet induced early obesity, white adipocyte hypertrophy and increased lipid accumulation in brown adipose tissue associated with sex-specific changes of the ECS's components in weanling rats. In male pups, maternal HF diet decreased CB1 and CB2 protein in subcutaneous adipose tissue. In female pups, maternal HF diet increased visceral and decreased subcutaneous CB1. In brown adipose tissue, maternal HF diet increased CB1 regardless of pup sex. In addition, maternal HF diet differentially changed oestrogen receptor across the adipose depots in male and female pups. The ECS and oestrogen signalling play an important role in lipogenesis, adipogenesis and thermogenesis, and we observed early changes in their targets in adipose depots of the offspring. The present findings provide insights into the involvement of the ECS in the developmental origins of metabolic disease induced by inadequate maternal nutrition in early life.
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Tecido Adiposo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Endocanabinoides/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/etiologia , Receptores de Canabinoides/metabolismo , Desmame , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Adiposidade , Fenômenos Fisiológicos da Nutrição Animal , Animais , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/efeitos adversos , Feminino , Lactação , Metabolismo dos Lipídeos , Masculino , Obesidade/metabolismo , Gravidez , Fenômenos Fisiológicos da Nutrição Pré-Natal , Ratos Wistar , Receptores de Estrogênio/metabolismo , Fatores Sexuais , TermogêneseRESUMO
Mounting evidence has shown that glutamatergic and endocannabinoid systems in the hypothalamus regulate mammalian food intake. Stimulation of hypothalamic mGluR1/5 and CB1 receptors induces hyperphagia suggesting a possible interaction between these systems to control food intake. In addition, synthesis of endocannabinoids has been reported after mGluR1/5 stimulation in the brain. The aim of this study was to examine the potential cannabinergic activity in the food intake induction by lateral hypothalamic stimulation of mGluR1/5. Wistar albino male rats received bilateral infusions in the lateral hypothalamus (LH) of: (i) vehicle; (ii) (RS)-2-Chloro-5-hidroxyphenylglycine (CHPG; mGluR1/5 agonist); (iii) 2-AG (CB1 endogenous agonist); (iv) AM251 (CB1 antagonist); (v) tetrahydrolipstatin (THL, 1.2µg; diacyl-glycerol lipase inhibitor); and (vi) combinations of CHPG + with the other aforementioned drugs. Food intake was evaluated the first two hours after drug administration. CHPG significantly increased food intake; whereas CHPG in combination with a dose of 2-AG (with no effects on food intake) greatly increased food ingestion compared to CHPG alone. The increase induced by CHPG in food intake was prevented with AM251 or THL. These results suggest that activation of mGluR1/5 in the lateral hypothalamus induces an orexigenic effect via activation of the endocannabinoid system.
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Ingestão de Alimentos , Endocanabinoides/fisiologia , Região Hipotalâmica Lateral/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Receptor de Glutamato Metabotrópico 5/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Animais , Ingestão de Alimentos/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Glicina/administração & dosagem , Glicina/análogos & derivados , Região Hipotalâmica Lateral/efeitos dos fármacos , Lactonas/administração & dosagem , Lipase Lipoproteica/antagonistas & inibidores , Masculino , Orlistate , Fenilacetatos/administração & dosagem , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor de Glutamato Metabotrópico 5/agonistas , Receptores de Glutamato Metabotrópico/agonistasRESUMO
BACKGROUND: Although in vivo studies have implicated endocannabinoids in metabolic dysfunction, little is known about direct, chronic activation of the endocannabinoid system (ECS) in human islets. Therefore, this study investigated the effects of prolonged exposure to cannabinoid agonists on human islet gene expression and function. METHODS: Human islets were maintained for 2 and 5 days in the absence or presence of CB1r (ACEA) or CB2r (JWH015) agonists. Gene expression was quantified by RT-PCR, hormone levels by radioimmunoassay and apoptosis by caspase activities. RESULTS: Human islets express an ECS, with mRNAs encoding the biosynthetic and degrading enzymes NAPE-PLD, FAAH and MAGL being considerably more abundant than DAGLα, an enzyme involved in 2-AG synthesis, or CB1 and CB2 receptor mRNAs. Prolonged activation of CB1r and CB2r altered expression of mRNAs encoding ECS components, but did not have major effects on islet hormone secretion. JWH015 enhanced insulin and glucagon content at 2 days, but had no effect after 5 days. Treatment with ACEA or JWH015 for up to 5 days did not have marked effects on islet viability, as assessed by morphology and caspase activities. CONCLUSIONS: Maintenance of human islets for up to 5 days in the presence of CB1 and CB2 receptor agonists causes modifications in ECS element gene expression, but does not have any major impact on islet function or viability. GENERAL SIGNIFICANCE: These data suggest that the metabolic dysfunction associated with over-activation of the ECS in obesity and diabetes in humans is unlikely to be secondary to impaired islet function.
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2-arachidonoylglycerol (2-AG) is an endogenous ligand of the cannabinoid CB1 receptor. This endocannabinoid and its hydrolyzing enzyme, monoacylglycerol lipase (MAGL), are present in encephalic regions related to psychiatric disorders, including the midbrain dorsolateral periaqueductal grey (dlPAG). The dlPAG is implicated in panic disorder and its stimulation results in defensive responses proposed as a model of panic attacks. The present work verified if facilitation of 2-AG signalling in the dlPAG counteracts panic-like responses induced by local chemical stimulation. Intra-dlPAG injection of 2-AG prevented panic-like response induced by the excitatory amino acid N-methyl-d-aspartate (NMDA). This effect was mimicked by the 2-AG hydrolysis inhibitor (MAGL preferring inhibitor) URB602. The anti-aversive effect of URB602 was reversed by the CB1 receptor antagonist, AM251. Additionally, a combination of sub-effective doses of 2-AG and URB602 also prevented NMDA-induced panic-like response. Finally, immunofluorescence assay showed a significant increase in c-Fos positive cells in the dlPAG after local administration of NMDA. This response was also prevented by URB602. These data support the hypothesis that 2-AG participates in anti-aversive mechanisms in the dlPAG and reinforce the proposal that facilitation of endocannabinoid signalling could be a putative target for developing additional treatments against panic and other anxiety-related disorders.
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Ácidos Araquidônicos/metabolismo , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Transtorno de Pânico/tratamento farmacológico , Transtorno de Pânico/metabolismo , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Animais , Compostos de Bifenilo/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Imunofluorescência , Masculino , N-Metilaspartato , Transtorno de Pânico/patologia , Substância Cinzenta Periaquedutal/patologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismoRESUMO
Anandamide and 2-arachidonoylglycerol (2-AG) are the two main endocannabinoids, exerting their effects by activating type 1 (CB1r) and type 2 (CB2r) cannabinoid receptors. Anandamide inhibits anxiety-like responses through the activation of CB1r in certain brain regions, including the dorsolateral periaqueductal gray (dlPAG). 2-AG also attenuates anxiety-like responses, although the neuroanatomical sites for these effects remained unclear. Here, we tested the hypothesis that enhancing 2-AG signaling in the dlPAG would induce anxiolytic-like effects. The mechanisms involved were also investigated. Male Wistar rats received intra-dlPAG injections of 2-AG, URB602 (inhibitor of the 2-AG hydrolyzing enzyme, mono-acylglycerol lipase--MGL), AM251 (CB1r antagonist) and AM630 (CB2r antagonist). The behavior was analyzed in the elevated plus maze after the following treatments. Exp. 1: vehicle (veh) or 2-AG (5 pmol, 50 pmol, and 500 pmol). Exp. 2: veh or URB602 (30 pmol, 100 pmol or 300 pmol). Exp. 3: veh or AM251 (100 pmol) followed by veh or 2-AG (50 pmol). Exp. 4: veh or AM630 (1000 pmol) followed by veh or 2-AG. Exp. 5: veh or AM251 followed by veh or URB602 (100 pmol). Exp. 6: veh or AM630 followed by veh or URB602. 2-AG (50 pmol) and URB602 (100 pmol) significantly increased the exploration of the open arms of the apparatus, indicating an anxiolytic-like effect. These behavioral responses were prevented by CB1r (AM251) or CB2r (AM630) antagonists. Our results showed that the augmentation of 2-AG levels in the dlPAG induces anxiolytic-like effects. The mechanism seems to involve both CB1r and CB2r receptors.