Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.036
Filtrar
2.
J Pharm Pharmacol ; 72(1): 84-91, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31722122

RESUMO

OBJECTIVES: To determine if diminished orthosteric agonist binding due to mutations in extracellular loops 1 or 2 of the cannabinoid receptor 1 (CB1 ) can be overcome by an allosteric modulator and restore agonist binding. METHODS: Binding assays were performed using a range of concentrations of orthosteric compound, in the presence or absence of a set concentration of the allosteric modulator PSNCBAM-1 to determine the EC50 in its absence or presence. KEY FINDINGS: Single mutations in extracellular loop 1 or 2 of CB1 showed weak or no binding of agonist CP55940 to the receptor. Interestingly, upon addition of the allosteric modulator PSNCBAM-1, this binding was restored typically to wild-type CB1 levels. In a few cases, the allosteric modulator ORG27569 was compared with PSNCBAM-1 for CP55940 binding and it also restored binding. Further, wild-type levels of inverse agonist bound the CB1 mutants in the absence of modulator, suggesting the mutants were originally folded like the wild type. CONCLUSIONS: Based on our findings, we provide evidence of a therapeutic application for allosteric modulators in situations where a mutation in the receptor may hinder its function. By utilizing allosteric modulators, restoration of orthosteric binding may be possible.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Cicloexanóis/farmacologia , Indóis/farmacologia , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Rimonabanto/farmacologia , Sítios de Ligação , Agonistas de Receptores de Canabinoides/metabolismo , Cicloexanóis/metabolismo , Células HEK293 , Humanos , Indóis/metabolismo , Ligantes , Mutação , Compostos de Fenilureia/metabolismo , Piperidinas/metabolismo , Ligação Proteica , Conformação Proteica , Piridinas/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto/metabolismo , Relação Estrutura-Atividade
3.
Biochemistry (Mosc) ; 84(8): 954-962, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31522677

RESUMO

Recent pharmacological findings regarding rimonabant, an anorectic and cannabinoid type 1 receptor (CB1R) antagonist, strongly suggest that some of its effects on the metabolic parameters and energy balance in rats are not related to the centrally mediated reduction in caloric intake. Instead, they may be associated with acute induction of glycogenolysis in the liver, in combination with transient increase in glucose oxidation and persistent increase in fat oxidation. It is possible that rimonabant produced direct short- or long-term stimulatory effect on these processes in primary and cultured rat cells. Rimonabant slightly stimulated ß-oxidation of long-chain fatty acids in cultured rat myocytes overexpressing glucose transporter isoform 4, as well as activated phosphorylation of adenosine monophosphate-dependent protein kinase (AMPK) in primary rat hepatocytes upon long-term incubation. However, short-term action of rimonabant failed to stimulate ß-oxidation in myocytes, myotubes, and hepatocytes, as well as to upregulate AMPK phosphorylation, glycogenolysis, and cAMP levels in hepatocytes. As a consequence, the acute effects of rimonabant on hepatic glycogen content (reduction) and total energy expenditure (increase) in rats fed with a standard diet cannot be explained by direct stimulation of glycogenolysis and fatty acid oxidation in muscles and liver. Rather, these effects seem to be centrally mediated.


Assuntos
Ácidos Graxos/metabolismo , Glicogenólise/efeitos dos fármacos , Fígado/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Oxirredução/efeitos dos fármacos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Rimonabanto/farmacologia , Adenilato Quinase/metabolismo , Animais , Linhagem Celular , AMP Cíclico/metabolismo , Glucose/metabolismo , Glicogênio/metabolismo , Hepatócitos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
4.
Mem Inst Oswaldo Cruz ; 114: e190062, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389521

RESUMO

BACKGROUND: Formation of schistosomal granulomata surrounding the ova can result in schistosomiasis-associated liver fibrosis (SSLF). The current standard of treatment is praziquantel (PZQ), which cannot effectively reverse SSLF. The role of the cannabinoid (CB) receptor family in liver fibrosis has recently been highlighted. OBJECTIVES: This study aimed to assess the therapeutic effect of CB1 receptor antagonism in reversing SSLF in a murine model of Schistosoma mansoni infection. METHODS: One hundred male Swiss albino mice were divided equally into five groups: healthy uninfected control (group I), infected control (group II), PZQ treated (group III), rimonabant (RIM) (SR141716, a CB1 receptor antagonist)-treated (group IV) and group V was treated with combined PZQ and RIM. Liver sections were obtained for histopathological examination, alpha-1 smooth muscle actin (α-SMA) immunostaining and assessment of CB1 receptor expression using real-time polymerase chain reaction (RT-PCR). FINDINGS: The most effective reduction in fibrotic marker levels and granuloma load was achieved by combined treatment with PZQ+RIM (group V): CB1 receptor expression (H = 26.612, p < 0.001), number of α-SMA-positive cells (F = 57.086, p < 0.001), % hepatic portal fibrosis (F = 42.849, p < 0.001) and number of granulomata (F = 69.088, p < 0.001). MAIN CONCLUSIONS: Combining PZQ with CB1 receptor antagonists yielded the best results in reversing SSLF. To our knowledge, this is the first study to test this regimen in S. mansoni infection.


Assuntos
Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/parasitologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Rimonabanto/farmacologia , Esquistossomose/tratamento farmacológico , Actinas/análise , Animais , Anti-Helmínticos/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Quimioterapia Combinada , Granuloma/parasitologia , Granuloma/patologia , Imuno-Histoquímica , Cirrose Hepática/patologia , Masculino , Camundongos , Miofibroblastos/parasitologia , Miofibroblastos/patologia , Praziquantel/farmacologia , Reprodutibilidade dos Testes , Esquistossomose/patologia , Resultado do Tratamento
5.
Am J Physiol Endocrinol Metab ; 317(3): E535-E547, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237449

RESUMO

CB1 receptor (CB1R) antagonism improves the deleterious effects of a high-fat diet (HFD) by reducing body fat mass and adipocyte cell size. Previous studies demonstrated that the beneficial effects of the CB1R antagonist rimonabant (RIM) in white adipose tissue (WAT) are partially due to an increase of mitochondria numbers and upregulation thermogenesis markers, suggesting an induction of WAT beiging. However, the molecular mechanism by which CB1R antagonism induces weight loss and WAT beiging is unclear. In this study, we probed for genes associated with beiging and explored longitudinal molecular mechanisms by which the beiging process occurs. HFD dogs received either RIM (HFD+RIM) or placebo (PL) (HFD+PL) for 16 wk. Several genes involved in beiging were increased in HFD+RIM compared with pre-fat, HFD, and HFD+PL. We evaluated lipolysis and its regulators including natriuretic peptide (NP) and its receptors (NPRs), ß-1 and ß-3 adrenergic receptor (ß1R, ß3R) genes. These genes were increased in WAT depots, accompanied by an increase in lipolysis in HFD+RIM. In addition, RIM decreased markers of inflammation and increased adiponectin receptors in WAT. We observed a small but significant increase in UCP1; therefore, we evaluated the newly discovered UCP1-independent thermogenesis pathway. We confirmed that SERCA2b and RYR2, the two key genes involved in this pathway, were upregulated in the WAT. Our data suggest that the upregulation of NPRs, ß-1R and ß-3R, lipolysis, and SERCA2b and RYR2 may be one of the mechanisms by which RIM promotes beiging and overall the improvement of metabolic homeostasis induced by RIM.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores do Fator Natriurético Atrial/efeitos dos fármacos , Proteína Desacopladora 1/efeitos dos fármacos , Animais , Cães , Expressão Gênica/efeitos dos fármacos , Inflamação/patologia , Inflamação/prevenção & controle , Resistência à Insulina , Masculino , Biogênese de Organelas , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Rimonabanto/farmacologia , Termogênese/efeitos dos fármacos , Termogênese/genética , Perda de Peso/efeitos dos fármacos
6.
Bull Exp Biol Med ; 167(1): 43-46, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31177459

RESUMO

We performed a comparative study of the cytotoxic effect of endocannabinoid N-arachidonoyl dopamine (AA-DA) on cultured stromal cells of ectopic and eutopic endometrium. It was found that AA-DA in the concentration range of 1-20 µM produces more selective cytotoxic effect on the stromal cells of the ectopic endometrium due to interaction with cannabinoid type 1 receptor. In concentrations below 1 µM, AA-DA stimulated the proliferation of stromal cells of the eutopic endometrium and did not affect the division of ectopic endometrium cells. This effect was realized due to its interaction with cannabinoid type 2 receptor.


Assuntos
Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dopamina/metabolismo , Endometriose/metabolismo , Endométrio/metabolismo , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Canfanos/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Endométrio/citologia , Feminino , Humanos , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo , Rimonabanto/farmacologia
7.
Pharmacol Biochem Behav ; 183: 72-79, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31202811

RESUMO

One of most formidable problems in the treatment of addiction is the high rate of relapse. The discovery of medicines to help mitigate relapse are aided by animal models that currently involve weeks of training and require surgical preparations and drug delivery devices. The present set of experiments was initiated to investigate a rapid 8-day screening method that utilizes food instead of intravenous drug administration. Male Sprague-Dawley rats were trained in a reinstatement paradigm in which every lever press produced a 45 mg food pellet concurrently paired with a light and tone. Behavior was subsequently extinguished with lever responses producing neither food nor food-associated stimuli. Reinstatement of responding was evaluated under conditions in which the first three responses of every 5 min time bin produced a food pellet along with food-associated stimuli. The mGlu5 receptor antagonists MPEP and MTEP produced a significant reduction in reinstatement while failing to alter responding where every response produced food. The cannabinoid CB1 receptor antagonist rimonabant and the mGlu2/3 receptor agonist LY379268 also selectively reduced reinstatement. Other compounds including clozapine, d-amphetamine, chlordiazepoxide, ABT-431, naltrexone and citalopram were without effect. The results suggest that relapse-like behavioral effects can be extended to non-pharmacological reinforcers. Drug effects demonstrated both behavioral and pharmacological specificity. The present experimental design thus allows for efficient and rapid assessment of the effects of drugs that might be useful in the treatment of addiction-associated relapse.


Assuntos
Comportamento Aditivo/tratamento farmacológico , Comportamento Aditivo/psicologia , Comportamento Animal/efeitos dos fármacos , Descoberta de Drogas/métodos , Modelos Animais , Aminoácidos/administração & dosagem , Aminoácidos/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Antagonistas de Receptores de Canabinoides/administração & dosagem , Antagonistas de Receptores de Canabinoides/farmacologia , Condicionamento Operante/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacologia , Extinção Psicológica/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Masculino , Piridinas/administração & dosagem , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Recidiva , Rimonabanto/administração & dosagem , Rimonabanto/farmacologia , Autoadministração , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Tiazóis/administração & dosagem , Tiazóis/farmacologia
8.
Inflammopharmacology ; 27(6): 1131-1142, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30945071

RESUMO

Osteoarthritis (OA) is characterized by cartilage degeneration, subchondral sclerosis, and pain. Cannabinoids have well-established anti-nociceptive properties in animal models of chronic pain. The aim of this study is to evaluate the anti-nociceptive effects of synthetic cannabinoids (WIN-55,212 and HU210) and the cannabinoid-like compound palmitoylethanolamide (PEA) in rat models of OA and to assess the role of cannabinoid receptor 1 (CB1) and the peroxisome proliferator-activated receptor α (PPARα) in mediating these effects. Intra-articular injection of monosodium iodoacetate (MIA) in the knee joint was used as a model of osteoarthritis. The von Frey filament test and weight-bearing difference were used to assess the anti-nociceptive effects of WIN-55,212, HU210, and PEA on MIA-induced OA in rats. Open-field locomotor activity system was used confirm the analgesic effects of those compounds. HU210, WIN55, 212, and PEA in a dose-dependent manner restored the paw withdrawal threshold (PWT) and the weight-bearing difference induced by MIA injection. SR141716A (a CB1 antagonist) significantly reversed the anti-nociceptive effects of all the administered drugs in terms of PWT. However, in terms of weight-bearing difference, SR141716A significantly reduced the anti-nociceptive effect of HU210 but not PEA or WIN55, 212. GW6471 (a PPARα antagonist) significantly reversed the anti-nociceptive effects of PEA but not those of HU210 or WIN55, 212. HU210, WIN55, 212 and PEA significantly restored the MIA-induced reduction in locomotor activity. In conclusions, both CB1 and PPARα receptors are involved in mediating pain in osteoarthritis. Therefore, targeting these receptors may be of great clinical value.


Assuntos
Analgésicos/farmacologia , Canabinoides/farmacologia , Osteoartrite/tratamento farmacológico , PPAR alfa/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Animais , Dronabinol/análogos & derivados , Dronabinol/farmacologia , Etanolaminas/farmacologia , Ácido Iodoacético/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Osteoartrite/fisiopatologia , Oxazóis/farmacologia , Ácidos Palmíticos/farmacologia , Ratos , Ratos Sprague-Dawley , Rimonabanto/farmacologia , Tirosina/análogos & derivados , Tirosina/farmacologia
9.
Pain ; 160(5): 1059-1069, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31008815

RESUMO

The taste of sucrose is commonly used to provide pain relief in newborn humans and is innately analgesic to neonatal rodents. In adulthood, sucrose remains a strong motivator to feed, even in potentially hazardous circumstances (ie, threat of tissue damage). However, the neurobiological mechanisms of this endogenous reward-pain interaction are unclear. We have developed a simple model of sucrose drinking-induced analgesia in Sprague-Dawley rats (6-10 weeks old) and have undertaken a behavioral and pharmacological characterization using the Hargreaves' test of hind-paw thermal sensitivity. Our results reveal an acute, potent, and robust inhibitory effect of sucrose drinking on thermal nociceptive behaviour that unlike the phenomenon in neonates is independent of endogenous opioid signalling and does not seem to operate through classical descending inhibition of the spinal cord circuitry. Experience of sucrose drinking had a conditioning effect whereby the apparent expectancy of sucrose enabled water alone (in euvolemic animals) to elicit a short-lasting placebo-like analgesia. Sweet taste alone, however, was insufficient to elicit analgesia in adult rats intraorally perfused with sucrose. Instead, the sucrose analgesia phenomenon only appeared after conditioning by oral perfusion in chronically cannulated animals. This sucrose analgesia was completely prevented by systemic dosing of the endocannabinoid CB1 receptor antagonist rimonabant. These results indicate the presence of an endogenous supraspinal analgesic circuit that is recruited by the context of rewarding drinking and is dependent on endocannabinoid signalling. We propose that this hedonic sucrose-drinking model may be useful for further investigation of the supraspinal control of pain by appetite and reward.


Assuntos
Hiperalgesia/terapia , Limiar da Dor/efeitos dos fármacos , Medula Espinal/fisiologia , Sacarose/uso terapêutico , Edulcorantes/uso terapêutico , Animais , Antagonistas de Receptores de Canabinoides/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Adjuvante de Freund/toxicidade , Temperatura Alta/efeitos adversos , Hiperalgesia/induzido quimicamente , Injeções Espinhais/métodos , Masculino , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Rimonabanto/farmacologia , Medula Espinal/efeitos dos fármacos , Privação de Água/fisiologia
10.
J Biol Chem ; 294(19): 7669-7681, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-30910812

RESUMO

Although cannabinoid receptor 1 (CB1) antagonists have been shown to attenuate diet-induced obesity (DIO) and associated inflammation, the precise molecular mechanisms involved are not clear. In the current study, we investigated the role of microRNA (miR) in the regulation of adipose tissue macrophage (ATM) phenotype following treatment of DIO mice with the CB1 antagonist SR141716A. DIO mice were fed high-fat diet (HFD) for 12 weeks and then treated daily with SR141716A (10 mg/kg) for 4 weeks while continuing HFD. Treated mice experienced weight loss, persistent reduction in fat mass, improvements in metabolic profile, and decreased adipose inflammation. CB1 blockade resulted in down-regulation of several miRs in ATMs, including the miR-466 family and miR-762. Reduced expression of the miR-466 family led to induction of anti-inflammatory M2 transcription factors KLF4 and STAT6, whereas down-regulation of miR-762 promoted induction of AGAP-2, a negative regulator of the neuroimmune retention cues, Netrin-1 and its coreceptor UNC5B. Furthermore, treatment of primary macrophages with SR141716A up-regulated KLF4 and STAT6, reduced secretion of Netrin-1, and increased migration toward the lymph node chemoattractant CCL19. These studies demonstrate for the first time that CB1 receptor blockade attenuates DIO-associated inflammation through alterations in ATM miR expression that promote M2 ATM polarization and macrophage egress from adipose tissue. The current study also identifies additional novel therapeutic targets for diet-induced obesity and metabolic disorder.


Assuntos
Tecido Adiposo/metabolismo , Quimiotaxia/efeitos dos fármacos , Gorduras na Dieta/efeitos adversos , Macrófagos/metabolismo , MicroRNAs/metabolismo , Obesidade/metabolismo , Receptor CB1 de Canabinoide/antagonistas & inibidores , Rimonabanto/farmacologia , Tecido Adiposo/patologia , Animais , Gorduras na Dieta/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/biossíntese , Macrófagos/patologia , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Receptor CB1 de Canabinoide/metabolismo , Fator de Transcrição STAT6/biossíntese
11.
PLoS One ; 14(3): e0209947, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30861005

RESUMO

Cannabis withdrawal upon discontinuation of long-term, heavy Cannabis use is reported in humans; however, methods to establish the nature and intensity of cannabinoid withdrawal, especially directly observable signs, have not been widely established. This study quantified activity in the home cage of rhesus monkeys and examined the extent to which activity can be used to quantify tolerance to and dependence on Δ9-tetrahydrocannabinol (Δ9-THC). Home-cage activity was measured in one group that received Δ9-THC (1 mg/kg s.c.) every 12 h (i.e., chronic Δ9-THC), and a second group that received Δ9-THC (0.1 mg/kg i.v.) once every 3 days (i.e., intermittent Δ9-THC). Treatment was temporarily discontinued in the chronic Δ9-THC group and the effects of rimonabant and Δ9-THC were examined in both groups. Activity counts were highest during the day (lights on 0600-2000 h) and were lower at night. Rimonabant (0.1-3.2 mg/kg i.v.) dose-dependently increased activity (maximum 20-fold) in the chronic Δ9-THC group but did not significantly alter activity in the intermittent Δ9-THC group. Δ9-THC (0.32-3.2 mg/kg i.v.) dose-dependently decreased activity counts (maximum 4-fold) in both groups but was somewhat more potent in the intermittent as compared with the Δ9-THC group. Discontinuation of Δ9-THC treatment resulted in an immediate (i.e., within 24 h) and time-related increase in activity. The time-related increase in home-cage activity upon abrupt discontinuation of chronic Δ9-THC treatment, as well as the effects of rimonabant to increase activity in monkeys receiving chronic, but not intermittent, Δ9-THC treatment, are consistent with signs of physical dependence on Δ9-THC in primates.


Assuntos
Dronabinol/efeitos adversos , Tolerância a Medicamentos , Alucinógenos/efeitos adversos , Atividade Motora/efeitos dos fármacos , Rimonabanto/administração & dosagem , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Administração Intravenosa , Animais , Modelos Animais de Doenças , Feminino , Alucinógenos/farmacologia , Humanos , Macaca mulatta , Masculino , Rimonabanto/farmacologia
12.
Neurosci Lett ; 701: 132-135, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-30742938

RESUMO

Δ9-Tetrahydrocannabinol (THC) is known to have various pharmacological effects mediated through activation of cannabinoid CB1 and CB2 receptors in rodents. In adult rats, 22- and 50-kHz ultrasonic vocalizations (USVs) serve as an effective communication system and as indicators of negative and positive states, respectively. The present study was performed to determine whether THC affects USVs in adult rats, and to determine the roles of cannabinoid receptors in these effects. THC (1, 3 mg/kg) was administered intraperitoneally to adult male Wistar rats 60 min before measurement of USVs. The CB1 antagonist, SR141716 (3, 6 mg/kg), or CB2 antagonist, AM630 (1, 10 mg/kg), was administered intraperitoneally 10 min before THC. USVs were measured during a 5-minute period without air puff stimulus or with air puff stimulus. THC did not affect 22- or 50-kHz USVs without air puff stimulus. On the other hand, THC significantly increased the number of 22-kHz USVs, but not 50-kHz USVs, after air puff stimulus. Moreover, SR141716 at 6 mg/kg, but not AM630 at either dose, inhibited the increase in number of 22-kHz USVs induced by THC after air puff stimulus. These results suggest that THC induced changes in sensitivity to aversive air puff stimuli through CB1 receptors, and as a result increased emission of 22-kHz USVs in rats.


Assuntos
Dronabinol/farmacologia , Estimulação Física , Ultrassom , Vocalização Animal/efeitos dos fármacos , Animais , Indóis/farmacologia , Masculino , Ratos , Ratos Wistar , Rimonabanto/farmacologia , Comportamento Social , Estresse Psicológico
13.
Cell ; 176(3): 636-648.e13, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30682372

RESUMO

Despite intensive efforts to discover highly effective treatments to eradicate tuberculosis (TB), it remains as a major threat to global human health. For this reason, new TB drugs directed toward new targets are highly coveted. MmpLs (Mycobacterial membrane proteins Large), which play crucial roles in transporting lipids, polymers and immunomodulators and which also extrude therapeutic drugs, are among the most important therapeutic drug targets to emerge in recent times. Here, crystal structures of mycobacterial MmpL3 alone and in complex with four TB drug candidates, including SQ109 (in Phase 2b-3 clinical trials), are reported. MmpL3 consists of a periplasmic pore domain and a twelve-helix transmembrane domain. Two Asp-Tyr pairs centrally located in this domain appear to be key facilitators of proton-translocation. SQ109, AU1235, ICA38, and rimonabant bind inside the transmembrane region and disrupt these Asp-Tyr pairs. This structural data will greatly advance the development of MmpL3 inhibitors as new TB drugs.


Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/ultraestrutura , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Membrana Transportadoras/ultraestrutura , Adamantano/análogos & derivados , Adamantano/metabolismo , Antituberculosos/química , Transporte Biológico , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Etilenodiaminas/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/ultraestrutura , Compostos de Fenilureia/metabolismo , Rimonabanto/metabolismo , Tuberculose/microbiologia
14.
Neurobiol Dis ; 125: 92-106, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30685352

RESUMO

Intellectual disability is the most limiting hallmark of Down syndrome, for which there is no gold-standard clinical treatment yet. The endocannabinoid system is a widespread neuromodulatory system involved in multiple functions including learning and memory processes. Alterations of this system contribute to the pathogenesis of several neurological and neurodevelopmental disorders. However, the involvement of the endocannabinoid system in the pathogenesis of Down syndrome has not been explored before. We used the best-characterized preclinical model of Down syndrome, the segmentally trisomic Ts65Dn model. In male Ts65Dn mice, cannabinoid type-1 receptor (CB1R) expression was enhanced and its function increased in hippocampal excitatory terminals. Knockdown of CB1R in the hippocampus of male Ts65Dn mice restored hippocampal-dependent memory. Concomitant with this result, pharmacological inhibition of CB1R restored memory deficits, hippocampal synaptic plasticity and adult neurogenesis in the subgranular zone of the dentate gyrus. Notably, the blockade of CB1R also normalized hippocampal-dependent memory in female Ts65Dn mice. To further investigate the mechanisms involved, we used a second transgenic mouse model overexpressing a single gene candidate for Down syndrome cognitive phenotypes, the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). CB1R pharmacological blockade similarly improved cognitive performance, synaptic plasticity and neurogenesis in transgenic male Dyrk1A mice. Our results identify CB1R as a novel druggable target potentially relevant for the improvement of cognitive deficits associated with Down syndrome.


Assuntos
Encéfalo/efeitos dos fármacos , Antagonistas de Receptores de Canabinoides/farmacologia , Cognição/efeitos dos fármacos , Síndrome de Down/metabolismo , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Fenótipo , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/efeitos dos fármacos , Rimonabanto/farmacologia
15.
Can J Physiol Pharmacol ; 97(2): 120-129, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30673308

RESUMO

In high-fat diet (HFD) induced nonalcoholic fatty liver disease (NAFLD), there is an increase in the endocannabinoid system activity, which significantly contributes to steatosis development. The aim of our study was to investigate the effects of cannabinoid receptor type 1 blockade on adipokine and proinflammatory cytokine content in adipose and hepatic tissue in mice with NAFLD. Male mice C57BL/6 were divided into a control group fed with a control diet for 20 weeks (C, n = 6) a group fed with a HFD for 20 weeks (HF, n = 6), a group fed with a control diet and treated with rimonabant after 18 weeks (R, n = 9), and a group fed with HFD and treated with rimonabant after 18 weeks (HFR, n = 10). Rimonabant significantly decreased leptin, resistin, apelin, visfatin, interleukin 6 (IL-6), and interferon-γ (IFN-γ) concentration in subcutaneous and visceral adipose tissue in the HFR group compared to the HF group (p < 0.01). Rimonabant reduced hepatic IL-6 and IFN-γ concentration as well as plasma glucose and insulin concentration and the homeostatic model assessment index in the HFR group compared to the HF group (p < 0.01). It can be concluded that the potential usefulness of CB1 blockade in the treatment of HFD-induced NAFLD is due to modulation of the adipokine profile and proinflammatory cytokines in both adipose tissues and liver as well as glucose metabolism.


Assuntos
Antagonistas de Receptores de Canabinoides/farmacologia , Citocinas/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptor CB1 de Canabinoide/antagonistas & inibidores , Rimonabanto/farmacologia , Adipocinas/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Glicemia/efeitos dos fármacos , Antagonistas de Receptores de Canabinoides/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Glucose/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Rimonabanto/uso terapêutico
16.
PLoS One ; 14(1): e0205781, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30645588

RESUMO

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-reexposure interventions, while those in the hippocampus have usually performed them after reexposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory reexposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after reexposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.


Assuntos
Tonsila do Cerebelo/fisiologia , Medo/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Receptor CB1 de Canabinoide/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Antagonistas de Receptores de Canabinoides/administração & dosagem , Condicionamento Clássico/efeitos dos fármacos , Maleato de Dizocilpina/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Modelos Animais , Ratos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/metabolismo , Rimonabanto/administração & dosagem , Fatores de Tempo
17.
Pharmacol Biochem Behav ; 177: 27-33, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30597181

RESUMO

Recently, multiple compounds have been synthesized that target the allosteric binding site(s) of CB1. These CB1 positive allosteric modulators may capture the benefits of cannabinoid receptor activation without unwanted psychoactive effects, such as sedation. For example, ZCZ011 blocks neuropathic pain, absent the catalepsy, sedation, and hypothermia caused by CB1 orthosteric modulators, including Δ9-tetrahydrocannabinol (THC). The primary goal of the present study was to evaluate the potential of ZCZ011 to attenuate somatic signs of cannabinoid withdrawal in mice. Mice were repeatedly administered THC (10 mg/kg, s.c.) or vehicle, and withdrawal was either precipitated using the CB1 antagonist rimonabant (3 mg/kg, i.p.) or elicited spontaneously via THC abstinence. ZCZ011 (≥10 mg/kg, i.p.) significantly attenuated somatic signs of withdrawal, including head twitches and paw tremors, but had no effect on locomotor activity or conditioned place preference. We next tested the antiulcerogenic properties of CB1 positive allosteric modulation. Mice were fasted for 22 h, administered ZCZ011, and gastric hemorrhages were induced with the nonsteroidal anti-inflammatory drug diclofenac sodium (100 mg/kg, p.o.). ZCZ011 alone had no effect on gastric ulceration, but ZCZ011 (≥10 mg/kg) blocked ulcer formation when combined with a subthreshold MAGL inhibitor (JZL184; 1 mg/kg, i.p.). Thus, CB1 positive allosteric modulation is a novel approach to treat cannabinoid dependence and gastric inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Benzodioxóis/uso terapêutico , Agonistas de Receptores de Canabinoides/farmacologia , Diclofenaco/farmacologia , Dronabinol/farmacologia , Gastrite/induzido quimicamente , Gastrite/tratamento farmacológico , Indóis/uso terapêutico , Piperidinas/uso terapêutico , Receptor CB1 de Canabinoide/metabolismo , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Tiofenos/uso terapêutico , Regulação Alostérica , Sítio Alostérico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Benzodioxóis/farmacologia , Agonistas de Receptores de Canabinoides/administração & dosagem , Diclofenaco/administração & dosagem , Dronabinol/administração & dosagem , Quimioterapia Combinada , Indóis/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Monoacilglicerol Lipases/antagonistas & inibidores , Úlcera Péptica Hemorrágica/induzido quimicamente , Úlcera Péptica Hemorrágica/tratamento farmacológico , Piperidinas/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Rimonabanto/farmacologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Tiofenos/farmacologia
18.
Acta Pharmacol Sin ; 40(3): 418-424, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29991708

RESUMO

Despite the apparent abundance of ligand-gated transient receptor potential vanilloid type 1 (TRPV1) and possible cross talk between the endocannabinoid and endovanilloid systems in the central nervous system (CNS), it is unclear what role TRPV1 receptor activation in CNS plays in neurobehavioral development. We previously reported that capsaicin or WIN55212-2 induces risk aversion in the plus-maze test, which was dependent on the gender and mouse strain used. In this study, pregnant BALBc mice were administered capsaicin (1.0 or 4.0 mg/kg, i.p.) during the second week of gestation. Developmental effects of prenatal exposure to capsaicin were assessed in neonates, and behavioral effects were assessed in adult offspring. Gender- and dose-specific variations in ultrasonic vocalizations, weight gain, righting reflex, and general activity of the pups were observed. Prenatal exposure to capsaicin altered plus-maze performance, especially with further exogenous capsaicin challenge. Furthermore, dose- and gender-specific effects were evident in the conditioned place preference/aversion paradigm following conditioning with capsaicin in adult animals. The capsaicin-induced aversion in the plus-maze test was enhanced by WIN55212-2 and blocked by pretreatment with vanilloid antagonist capsazepine or the CB1 receptor antagonist rimonabant, demonstrating an interaction between the endocannabinoid and endovanilloid systems in CNS. Taken together, the interaction between the endocannabinoid and endovanilloid signaling systems can be exploited for therapeutic applications in health and disease.


Assuntos
Comportamento Animal/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/farmacologia , Capsaicina/farmacologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Receptores de Canabinoides/metabolismo , Animais , Benzoxazinas/farmacologia , Agonistas de Receptores de Canabinoides/administração & dosagem , Capsaicina/administração & dosagem , Capsaicina/análogos & derivados , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Injeções Intraperitoneais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Morfolinas/farmacologia , Naftalenos/farmacologia , Gravidez , Receptor Cross-Talk , Rimonabanto/farmacologia , Canais de Cátion TRPV/agonistas
19.
Physiol Behav ; 199: 282-291, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30502357

RESUMO

Circulating levels of bacterial lipopolysaccharide (LPS) or endotoxin are chronically elevated in obesity (metabolic endotoxemia), resulting in low-grade inflammation. Metabolic endotoxemia has been identified as a triggering factor for obesity-associated metabolic complications such as insulin resistance. Furthermore, LPS has been shown to modulate endocannabinoid synthesis and notably to induce cannabinoid receptor type-1 (CB1) ligand synthesis. CB1 activation promotes inflammation, increases food intake and impairs insulin signaling. Therefore, we hypothesized that LPS acts through a CB1-dependent mechanism to aggravate inflammation and promote insulin resistance. Male Wistar rats fed a chow diet were implanted with mini-osmotic pumps delivering a low dose of LPS (n = 20; 12.5 µg/kg body weight (BW)/hr.) or saline (n = 10) continuously for six weeks. LPS-treated rats were injected daily with a CB1 antagonist (Rimonabant, SR141716A; 3 mg/kg, intraperitoneal (ip); LPS + CB1x; n = 10) or vehicle (1 mL/kg, LPS; n = 10). Control and LPS rats' food intake was matched to the LPS + CB1x group level. Despite no significant differences in body weight among groups, chronic exposure to low-level LPS altered hepatic endocannabinoid signaling, increased inflammation, and impaired insulin sensitivity and insulin clearance (P < 0.05). CB1 inhibition significantly attenuated LPS signaling (P < 0.05), which attenuated LPS-induced metabolic alterations. Therefore, we concluded that CB1 contributes to LPS-mediated inflammation and insulin resistance, suggesting that blocking CB1 signaling may have therapeutic benefits in reducing inflammation-induced metabolic abnormalities.


Assuntos
Endotoxemia/metabolismo , Inflamação/metabolismo , Resistência à Insulina/fisiologia , Receptor CB1 de Canabinoide/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Antagonistas de Receptores de Canabinoides/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Endotoxemia/induzido quimicamente , Inflamação/induzido quimicamente , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Rimonabanto/farmacologia , Transdução de Sinais/efeitos dos fármacos
20.
FASEB J ; 33(3): 4314-4326, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30566396

RESUMO

The overactivity of cannabinoid 1 receptor (CB1R) is associated with obesity and type 2 diabetes. First-generation CB1R antagonists, such as rimonabant, offered therapeutic advantages for the control of obesity and related metabolic abnormalities, but their therapeutic potential was limited by undesirable neuropsychiatric side effects. Here, we evaluated AJ5012 as a novel potent peripheral CB1R antagonist and, using this antagonist, investigated the role of peripheral CB1R on adipose tissue inflammation in obese mouse models. AJ5012 had a high degree of CB1R and cannabinoid 2 receptor selectivity but a low brain:plasma concentration ratio without eliciting centrally mediated neurobehavioral effects. In diet-induced obese (DIO) mice, AJ5012 did not reduce food intake but did induce a significant weight loss, likely owing to an increased energy expenditure. It was as effective as rimonabant for the improvement of hormonal or metabolic abnormalities, glycemic control, and insulin sensitivity. The treatment of DIO and leptin receptor-deficient mice with AJ5012 also exhibited effects comparable to rimonabant for the prevention of macrophage infiltration, activation of the nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome, and production of proinflammatory cytokines, which resulted in the suppression of adipose tissue inflammation. In addition to macrophage, activation of CB1R in 3T3-L1 adipocytes induced the expression of proinflammatory genes, which was fully inhibited by AJ5012. Our findings identified AJ5012 as a novel peripheral CB1R antagonist and suggest that peripheral CB1R blockade might break the links between insulin resistance and adipose tissue inflammation.-Han, J. H., Shin, H., Park, J.-Y., Rho, J. G., Son, D. H., Kim, K. W., Seong, J. K., Yoon, S.-H., Kim, W. A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Receptor CB1 de Canabinoide/antagonistas & inibidores , Células 3T3 , Tecido Adiposo/metabolismo , Animais , Células CHO , Cricetulus , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Resistência à Insulina/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Células RAW 264.7 , Receptor CB2 de Canabinoide/metabolismo , Rimonabanto/metabolismo , Perda de Peso/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA