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1.
Cells ; 13(5)2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38474425

RESUMO

Cannabis use stimulates calorie intake, but epidemiological studies show that people who regularly use it are leaner than those who don't. Two explanations have been proposed for this paradoxical finding. One posits that Δ9-tetrahydrocannabinol (THC) in cannabis desensitizes adipose CB1 cannabinoid receptors, stopping their stimulating effects on lipogenesis and adipogenesis. Another explanation is that THC exposure in adolescence, when habitual cannabis use typically starts, produces lasting changes in the developing adipose organ, which impacts adult systemic energy use. Here, we consider these possibilities in the light of a study which showed that daily THC administration in adolescent mice produces an adult metabolic phenotype characterized by reduced fat mass, partial resistance to obesity and dyslipidemia, and impaired thermogenesis and lipolysis. The phenotype, whose development requires activation of CB1 receptors in differentiated adipocytes, is associated with overexpression of myocyte proteins in the adipose organ with unchanged CB1 expression. We propose that adolescent exposure to THC causes lasting adipocyte dysfunction and the consequent emergence of a metabolic state that only superficially resembles healthy leanness. A corollary of this hypothesis, which should be addressed in future studies, is that CB1 receptors and their endocannabinoid ligands may contribute to the maintenance of adipocyte differentiation during adolescence.


Assuntos
Cannabis , Endocanabinoides , Humanos , Camundongos , Animais , Adolescente , Endocanabinoides/metabolismo , Obesidade/metabolismo , Adipócitos/metabolismo , Receptores de Canabinoides/metabolismo , Adiposidade
2.
Int J Mol Sci ; 25(3)2024 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-38339171

RESUMO

Resistant migraine characterizes those patients who have failed at least three classes of migraine prophylaxis. These difficult-to-treat patients are likely to be characterized by a high prevalence of psychological disturbances. A dysfunction of the endocannabinoid system (ECS), including alteration in the levels of endocannabinoid congeners, may underlie several psychiatric disorders and the pathogenesis of migraines. Here we explored whether the peripheral gene expression of major components of the ECS and the plasma levels of endocannabinoids and related lipids are associated with psychological disorders in resistant migraine. Fifty-one patients (age = 46.0 ± 11.7) with resistant migraine received a comprehensive psychological evaluation according to the DSM-5 criteria. Among the patients, 61% had personality disorders (PD) and 61% had mood disorders (MD). Several associations were found between these psychological disorders and peripheral ECS alterations. Lower plasma levels of palmitoiletanolamide (PEA) were found in the PD group compared with the non-PD group. The MD group was characterized by lower mRNA levels of diacylglycerol lipase α (DAGLα) and CB2 (cannabinoid-2) receptor. The results suggest the existence of peripheral dysfunction in some components of the ECS and an alteration in plasma levels of PEA in patients with resistant migraine and mood or personality disorders.


Assuntos
Transtornos Mentais , Transtornos de Enxaqueca , Humanos , Adulto , Pessoa de Meia-Idade , Endocanabinoides/metabolismo , Estudos Transversais , Receptores de Canabinoides/metabolismo , Transtornos da Personalidade , Personalidade , Transtornos de Enxaqueca/genética
3.
Sci Total Environ ; 918: 170679, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38325485

RESUMO

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q) is a quinone derivative of a common tire additive 6PPD, whose occurrence has been widely reported both in the environment and human bodies including in adults, pregnant women and children. Yet, knowledge on the potential intestinal toxicity of 6PPD-Q in mammals at environmentally relevant dose remain unknown. In this study, the effects of 6PPD-Q on the intestines of adult ICR mice were evaluated by orally administering environmentally relevant dose or lower levels of 6PPD-Q (0.1, 1, 10, and 100 µg/kg) for 21 days. We found that 6PPD-Q disrupted the integrity of the intestinal barrier, mostly in the jejunum and ileum, but not in the duodenum or colon, in a dose-dependent manner. Moreover, intestinal inflammation manifested with elevated levels of TNF-α, IL-1, and IL-6 mostly observed in doses at 10 and 100 µg/kg. Using reverse target screening technology combining molecular dynamic simulation modeling we identified key cannabinoid receptors including CNR2 activation to be potentially mediating the intestinal inflammation induced by 6PPD-Q. In summary, this study provides novel insights into the toxic effects of emerging contaminant 6PPD-Q on mammalian intestines and that the chemical may be a cannabinoid receptor agonist to modulate inflammation.


Assuntos
Intestinos , Jejuno , Gravidez , Criança , Feminino , Humanos , Animais , Camundongos , Jejuno/metabolismo , Receptores de Canabinoides/metabolismo , Camundongos Endogâmicos ICR , Íleo/metabolismo , Inflamação/induzido quimicamente , Quinonas , Mamíferos
4.
Transl Psychiatry ; 14(1): 101, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38374108

RESUMO

G protein-coupled receptor 55 (GPR55) has been thought to be a putative cannabinoid receptor. However, little is known about its functional role in cannabinoid action and substance use disorders. Here we report that GPR55 is predominantly found in glutamate neurons in the brain, and its activation reduces self-administration of cocaine and nicotine in rats and mice. Using RNAscope in situ hybridization, GPR55 mRNA was identified in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons, with no detection in midbrain dopamine (DA) neurons. Immunohistochemistry detected a GPR55-like signal in both wildtype and GPR55-knockout mice, suggesting non-specific staining. However, analysis using a fluorescent CB1/GPR55 ligand (T1117) in CB1-knockout mice confirmed GPR55 binding in glutamate neurons, not in midbrain DA neurons. Systemic administration of the GPR55 agonist O-1602 didnt impact ∆9-THC-induced analgesia, hypothermia and catalepsy, but significantly mitigated cocaine-enhanced brain-stimulation reward caused by optogenetic activation of midbrain DA neurons. O-1602 alone failed to alter extracellar DA, but elevated extracellular glutamate, in the nucleus accumbens. In addition, O-1602 also demonstrated inhibitory effects on cocaine or nicotine self-administration under low fixed-ratio and/or progressive-ratio reinforcement schedules in rats and wildtype mice, with no such effects observed in GPR55-knockout mice. Together, these findings suggest that GPR55 activation may functionally modulate drug-taking and drug-seeking behavior possibly via a glutamate-dependent mechanism, and therefore, GPR55 deserves further study as a new therapeutic target for treating substance use disorders.


Assuntos
Canabidiol , Cocaína , Receptores de Canabinoides , Transtornos Relacionados ao Uso de Substâncias , Animais , Camundongos , Ratos , Canabidiol/análogos & derivados , Cocaína/farmacologia , Neurônios Dopaminérgicos/metabolismo , Ácido Glutâmico/metabolismo , Camundongos Knockout , Nicotina/farmacologia , Preparações Farmacêuticas/metabolismo , Receptores de Canabinoides/metabolismo , Receptores Acoplados a Proteínas G/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/metabolismo
5.
Int J Mol Sci ; 25(3)2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38338960

RESUMO

The lipid endocannabinoid system has recently emerged as a novel therapeutic target for several inflammatory and tissue-damaging diseases, including those affecting the cardiovascular system. The primary targets of cannabinoids are cannabinoid type 1 (CB1) and 2 (CB2) receptors. The CB2 receptor is expressed in the cardiomyocytes. While the pathological changes in the myocardium upregulate the CB2 receptor, genetic deletion of the receptor aggravates the changes. The CB2 receptor plays a crucial role in attenuating the advancement of myocardial infarction (MI)-associated pathological changes in the myocardium. Activation of CB2 receptors exerts cardioprotection in MI via numerous molecular pathways. For instance, delta-9-tetrahydrocannabinol attenuated the progression of MI via modulation of the CB2 receptor-dependent anti-inflammatory mechanisms, including suppression of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1ß. Through similar mechanisms, natural and synthetic CB2 receptor ligands repair myocardial tissue damage. This review aims to offer an in-depth discussion on the ameliorative potential of CB2 receptors in myocardial injuries induced by a variety of pathogenic mechanisms. Further, the modulation of autophagy, TGF-ß/Smad3 signaling, MPTP opening, and ROS production are discussed. The molecular correlation of CB2 receptors with cardiac injury markers, such as troponin I, LDH1, and CK-MB, is explored. Special attention has been paid to novel insights into the potential therapeutic implications of CB2 receptor activation in MI.


Assuntos
Canabinoides , Infarto do Miocárdio , Receptor CB1 de Canabinoide , Humanos , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Canabinoides/metabolismo , Endocanabinoides/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Receptores de Canabinoides/metabolismo , Dronabinol/farmacologia
6.
Biochem Pharmacol ; 222: 116052, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38354957

RESUMO

The cannabinoid CB1 receptor (CB1) is a G protein-coupled receptor (GPCR) with widespread expression in the central nervous system. This canonically G⍺i/o-coupled receptor mediates the effects of Δ9-tetrahydrocannabinol (THC) and synthetic cannabinoid receptor agonists (SCRAs). Recreational use of SCRAs is associated with serious adverse health effects, making pharmacological research into these compounds a priority. Several studies have hypothesised that signalling bias may explain the different toxicological profiles between SCRAs and THC. Previous studies have focused on bias between G protein activation measured by cyclic adenosine monophosphate (cAMP) inhibition and ß-arrestin translocation. In contrast, the current study characterises bias between G⍺ subtypes of the G⍺i/o family and ß-arrestins; this method facilitates a more accurate assessment of ligand bias by assessing signals that have not undergone major amplification. We have characterised G protein dissociation and translocation of ß-arrestin 1 and 2 using real-time BRET reporters. The responses produced by each SCRA across the G protein subtypes tested were consistent with the responses produced by the reference ligand AMB-FUBINACA. Ligand bias was probed by applying the operational analysis to determine biases within the G⍺i/o family, and between G protein subtypes and ß-arrestins. Overall, these results confirm SCRAs to be balanced, high-efficacy ligands compared to the low efficacy ligand THC, with only one SCRA, 4CN-MPP-BUT7IACA, demonstrating statistically significant bias in one pathway comparison (towards ß-arrestin 1 when compared with G⍺oA/oB). This suggests that the adverse effects caused by SCRAs are due to high potency and efficacy at CB1, rather than biased agonism.


Assuntos
Agonistas de Receptores de Canabinoides , Canabinoides , Agonistas de Receptores de Canabinoides/farmacologia , Agonistas de Receptores de Canabinoides/metabolismo , beta-Arrestinas/metabolismo , Receptores de Canabinoides/metabolismo , beta-Arrestina 1/metabolismo , Ligantes , Proteínas de Ligação ao GTP/metabolismo , Canabinoides/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo
7.
Neurochem Res ; 49(5): 1278-1290, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38368587

RESUMO

Social isolation is a state of lack of social connections, involving the modulation of different molecular signalling cascades and associated with high risk of mental health issues. To investigate if and how gene expression is modulated by social experience at the central level, we analyzed the effects of 5 weeks of social isolation in rats focusing on endocannabinoid system genes transcription in key brain regions involved in emotional control. We observed selective reduction in mRNA levels for fatty acid amide hydrolase (Faah) and cannabinoid receptor type 1 (Cnr1) genes in the amygdala complex and of Cnr1 in the prefrontal cortex of socially isolated rats when compared to controls, and these changes appear to be partially driven by trimethylation of Lysine 27 and acetylation of Lysine 9 at Histone 3. The alterations of Cnr1 transcriptional regulation result also directly correlated with those of oxytocin receptor gene. We here suggest that to counteract the effects of SI, it is of relevance to restore the endocannabinoid system homeostasis via the use of environmental triggers able to revert those epigenetic mechanisms accounting for the alterations observed.


Assuntos
Endocanabinoides , Lisina , Ratos , Animais , Endocanabinoides/metabolismo , Amidoidrolases/genética , Receptores de Canabinoides/metabolismo , Isolamento Social , Receptor CB1 de Canabinoide/genética
8.
J Chem Inf Model ; 64(3): 761-774, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38215394

RESUMO

Metal complexes exhibit a diverse range of coordination geometries, representing novel privileged scaffolds with convenient click types of preparation inaccessible for typical carbon-centered organic compounds. Herein, we explored the opportunity to identify biologically active organometallic complexes by reverse docking of a rigid, minimum-size octahedral organoruthenium scaffold against thousands of protein-binding pockets. Interestingly, cannabinoid receptor type 1 (CB1) was identified based on the docking scores and the degree of overlap between the docked organoruthenium scaffold and the hydrophobic scaffold of the cocrystallized ligand. Further structure-based optimization led to the discovery of organoruthenium complexes with nanomolar binding affinities and high selectivity toward CB2. Our work indicates that octahedral organoruthenium scaffolds may be advantageous for targeting the large and hydrophobic binding pockets and that the reverse docking approach may facilitate the discovery of novel privileged scaffolds, such as organometallic complexes, for exploring chemical space in lead discovery.


Assuntos
Desenho de Fármacos , Receptor CB2 de Canabinoide , Receptores de Canabinoides/química , Receptores de Canabinoides/metabolismo , Ligação Proteica , Ligantes , Receptor CB2 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/metabolismo
9.
Eur J Med Res ; 29(1): 49, 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38216984

RESUMO

Synthetic cannabinoids (SCs) are chemically classified as psychoactive substances that target the endocannabinoid system in many body organs. SCs can initiate pathophysiological changes in many tissues which can be severe enough to damage the normal functionality of our body systems. The majority of SCs-related side effects are mediated by activating Cannabinoid Receptor 1 (CB1R) and Cannabinoid Receptor 2 (CB2R). The activation of these receptors can enkindle many downstream signalling pathways, including oxidative stress, inflammation, and apoptosis that ultimately can produce deleterious changes in many organs. Besides activating the cannabinoid receptors, SCs can act on non-cannabinoid targets, such as the orphan G protein receptors GPR55 and GPR18, the Peroxisome Proliferator-activated Receptors (PPARs), and the Transient receptor potential vanilloid 1 (TRPV1), which are broadly expressed in the brain and the heart and their activation mediates many pharmacological effects of SCs. In this review, we shed light on the multisystem complications found in SCs abusers, particularly discussing their neurologic, cardiovascular, renal, and hepatic effects, as well as highlighting the mechanisms that intermediate SCs-related pharmacological and toxicological consequences to provide comprehensive understanding of their short and long-term systemic effects.


Assuntos
Canabinoides , Humanos , Canabinoides/toxicidade , Canabinoides/metabolismo , Endocanabinoides/metabolismo , Receptores de Canabinoides/metabolismo , Transdução de Sinais
10.
Cannabis Cannabinoid Res ; 9(1): 12-20, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38174983

RESUMO

Introduction: The endocannabinoid system (ECS) mediates the actions of cannabis and has been implicated in playing critical roles in key developmental events, including axon guidance. Although several recent studies have demonstrated ECS involvement in neurodevelopment, an emphasis on its putative role in axon guidance has not been reviewed comprehensively. Objective: The purpose of this literature review is to evaluate the interrelationships between the ECS and axon guidance. Methodology: This literature review analyzes existing literature demonstrating the normal role of endocannabinoid (eCB) signaling in axon guidance, with evidence from diverse animal models. Studies were obtained from a search strategy involving terms related to the ECS and axon guidance, and cross-checking cited literature to ensure a complete evaluation. Discussion: Cannabinoid receptors, as well as eCB synthesis and degradation machinery, appear necessary for normal axon guidance during neurodevelopment. Genetic and/or pharmacological disruption of eCB signaling results in axon growth and guidance errors, implying high sensitivity to exogenous cannabinoids. Conclusion: Overall, this review highlights the intricate connections between the ECS and axon guidance in normal neurodevelopment. The mechanistic evidence discussed suggests that alterations of the ECS through genetic and pharmacological interference disrupt its normal functioning and by extension its normal role in regulating neural circuitry formation. A comprehensive understanding of this topic will be valuable in potentially uncovering the mechanisms responsible for the neurodevelopmental defects associated with pre-natal cannabis use.


Assuntos
Canabinoides , Cannabis , Alucinógenos , Animais , Endocanabinoides/metabolismo , Orientação de Axônios , Receptores de Canabinoides/metabolismo , Agonistas de Receptores de Canabinoides
11.
Can J Physiol Pharmacol ; 102(3): 218-227, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37976474

RESUMO

Tramadol, an analgesic classified as an "atypical opioid", exhibits both opioid and non-opioid mechanisms of action. This study aimed to explore these mechanisms, specifically the opioid-, cannabinoid-, nitric oxide-, and potassium channel-based mechanisms, which contribute to the peripheral antinociception effect of tramadol, in an experimental rat model. The nociceptive threshold was determined using paw pressure withdrawal. To examine the mechanisms of action, several substances were administered intraplantarly: naloxone, a non-selective opioid antagonist (50 µg/paw); AM251 (80 µg/paw) and AM630 (100 µg/paw) as the selective antagonists for types 1 and 2 cannabinoid receptors, respectively; nitric oxide synthase inhibitors L-NOArg, L-NIO, L-NPA, and L-NIL (24 µg/paw); and the enzyme inhibitors of guanylatocyclase and phosphodiesterase of cGMP, ODQ, and zaprinast. Additionally, potassium channel blockers glibenclamide, tetraethylammonium, dequalinium, and paxillin were used. The results showed that opioid and cannabinoid receptor antagonists did not reverse tramadol's effects. L-NOarg, L-NIO, and L-NPA partially reversed antinociception, while ODQ completely reversed, and zaprinast enhanced tramadol's antinociception effect. Notably, glibenclamide blocked tramadol's antinociception in a dose-dependent manner. These findings suggest that tramadol's peripheral antinociception effect is likely mediated by the nitrergic pathway and sensitive ATP potassium channels, rather than the opioid and cannabinoid pathways.


Assuntos
Canabinoides , Tramadol , Ratos , Animais , Analgésicos Opioides/farmacologia , Tramadol/farmacologia , Tramadol/uso terapêutico , Óxido Nítrico/metabolismo , Ratos Wistar , Canais de Potássio/metabolismo , Hiperalgesia/metabolismo , Nitroarginina , Receptores de Canabinoides/metabolismo , Glibureto , Analgésicos/farmacologia , Analgésicos/uso terapêutico , GMP Cíclico/metabolismo , Canabinoides/efeitos adversos
12.
J Nutr Biochem ; 123: 109484, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37866428

RESUMO

n-3 polyunsaturated fatty acids (PUFA) have shown to exert beneficial effects in the treatment of nonalcoholic fatty liver disease (NAFLD). Supplements of n-3 PUFA occur in either phospholipid or triacylglycerol form. The present study aimed to compare whether the different n-3 PUFA of marine-origin, namely krill oil, DHA/EPA-phospholipid (PL), and EPA/DHA-triacylglycerol (TAG) forms had differential abilities to ameliorate NAFLD. The NAFLD model was established in mice fed a high-fat and high-cholesterol diet (HFD). The mice showed evidence of weight gain, dyslipidemia, insulin resistance and hepatic steatosis after 9 weeks of HFD, while the three forms of the n-3 PUFA reduced hepatic TAG accumulation, fatty liver and improved insulin instance, and hepatic biomarkers after 9 weeks of intervention. Of these, krill oil intervention significantly reduced adipocyte hypertrophy and hepatic steatosis in comparison with DHA/EPA-PL and EPA/DHA-TAG groups. Importantly, only krill oil intervention significantly reduced serum alanine transaminase, aspartate transaminase concentrations and low-density lipoprotein-cholesterol, compared with the HFD group. Supplemental n-3 PUFA lowered circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) concentrations, compared with the HFD group, which was associated with down-regulating CB1 and upregulating adiponectin expressions in adipose tissue. Besides, targeted lipidomic analyses indicated that the increased adiponectin levels were accompanied by reductions in hepatic ceramide levels. The reduced ceramide levels were associated with inhibiting lipid synthesis and increasing fatty acid ß-oxidation, finally inhibiting TAG accumulation in the liver. Through mediating CB1/adiponectin/ceramide pathway, the present study suggested that administration of krill oil had superior health effects in the therapy of NAFLD in comparison with DHA/EPA-PL and EPA/DHA-TAG.


Assuntos
Ácidos Graxos Ômega-3 , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Ácidos Graxos Ômega-3/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosfolipídeos/metabolismo , Adiponectina/metabolismo , Triglicerídeos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Fígado/metabolismo , Ácidos Graxos Insaturados/metabolismo , Colesterol/metabolismo , Receptores de Canabinoides/metabolismo , Ácidos Graxos/metabolismo
13.
Artigo em Inglês | MEDLINE | ID: mdl-38113964

RESUMO

In addition to their well-known classical effects, cannabinoid CB1 and CB2 receptors have also been involvement in both deleterious and protective actions on the heart under various pathological conditions. While the potential therapeutic applications of the endocannabinoid system in the context of cardiovascular function are indeed a viable prospect, significant debate exists within the literature regarding whether CB1, CB2, or a combination of both receptors exert a favorable influence on cardiac function. Hence, the aim of this study was to investigate the effects of CB1 + CB2 or CB2 agonists on cardiac excitation-contraction (E-C) coupling, utilizing fish (Brycon amazonicus) as an experimental model. The CB2 agonist elicited marked positive inotropic and lusitropic responses in isolated ventricular myocardium, induced cyclic adenosine 3',5'-monophosphate (cAMP) production, and upregulated critical Ca2+ handling proteins, such as sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and Na+/Ca2+ exchanger (NCX). Our current study demonstrated, for the first time, that CB2 receptor activation-induced effects improved the efficiency of Ca2+ cycling, excitation-contraction coupling (E-C coupling), and cardiac performance in under physiological conditions. Hence, CB2 receptors could be considered a potential therapeutic target for modulating cardiac contractile dysfunctions.


Assuntos
Canabinoides , Caraciformes , Animais , Receptores de Canabinoides/metabolismo , Miocárdio/metabolismo , Coração , Acoplamento Excitação-Contração , Agonistas de Receptores de Canabinoides/metabolismo , Agonistas de Receptores de Canabinoides/farmacologia , Receptor CB2 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/metabolismo
14.
Int J Mol Sci ; 24(21)2023 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-37958673

RESUMO

The endocannabinoid system (ECS) is a new target for the development of retinal disease therapeutics, whose pathophysiology involves neurodegeneration and neuroinflammation. The endocannabinoid 2-arachidonoylglycerol (2-AG) affects neurons and microglia by activating CB1/CB2 cannabinoid receptors (Rs). The aim of this study was to investigate the effects of 2-AG on the CB1R expression/downregulation and retinal neurons/reactive microglia, when administered repeatedly (4 d), in three different paradigms. These involved the 2-AG exogenous administration (a) intraperitoneally (i.p.) and (b) topically and (c) by enhancing the 2-AG endogenous levels via the inhibition (AM11920, i.p.) of its metabolic enzymes (MAGL/ABHD6). Sprague Dawley rats were treated as mentioned above in the presence or absence of CB1/CB2R antagonists and the excitatory amino acid, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Immunohistochemistry, Western blot and a 2-AG level analyses were performed. The 2-AG repeated treatment (i.p.) induced the CB1R downregulation, abolishing its neuroprotective actions. However, 2-AG attenuated the AMPA-induced activation of microglia via the CB2R, as concurred by the AM630 antagonist effect. Topically administered 2-AG was efficacious as a neuroprotectant/antiapoptotic and anti-inflammatory agent. AM11920 increased the 2-AG levels providing neuroprotection against excitotoxicity and reduced microglial activation without affecting the CB1R expression. Our findings show that 2-AG, in the three paradigms studied, displays differential pharmacological profiles in terms of the downregulation of the CB1R and neuroprotection. All treatments, however, attenuated the activation of microglia via the CB2R activation, supporting the anti-inflammatory role of 2-AG in the retina.


Assuntos
Endocanabinoides , Microglia , Ratos , Animais , Endocanabinoides/farmacologia , Endocanabinoides/metabolismo , Receptores de Canabinoides/metabolismo , Microglia/metabolismo , Ratos Sprague-Dawley , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo , Retina/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo
15.
Int J Mol Sci ; 24(21)2023 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-37958761

RESUMO

Endocannabinoids were implicated in a variety of pathological conditions including anxiety and are considered promising new targets for anxiolytic drug development. The optimism concerning the potentials of this system for anxiolysis is probably justified. However, the complexity of the mechanisms affected by endocannabinoids, and discrepant findings obtained with various experimental approaches makes the interpretation of research results difficult. Here, we review the anxiety-related effects of the three main interventions used to study the endocannabinoid system: pharmacological agents active at endocannabinoid-binding sites present on both the cell membrane and in the cytoplasm, genetic manipulations targeting cannabinoid receptors, and function-enhancers represented by inhibitors of endocannabinoid degradation and transport. Binding-site ligands provide inconsistent findings probably because they activate a multitude of mechanisms concomitantly. More robust findings were obtained with genetic manipulations and particularly with function enhancers, which heighten ongoing endocannabinoid activation rather than affecting all mechanisms indiscriminately. The enhancement of ongoing activity appears to ameliorate stress-induced anxiety without consistent effects on anxiety in general. Limited evidence suggests that this effect is achieved by promoting active coping styles in critical situations. These findings suggest that the functional enhancement of endocannabinoid signaling is a promising drug development target for stress-related anxiety disorders.


Assuntos
Canabinoides , Humanos , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Endocanabinoides/metabolismo , Moduladores de Receptores de Canabinoides/metabolismo , Ansiedade/tratamento farmacológico , Transtornos de Ansiedade , Receptores de Canabinoides/metabolismo , Adaptação Psicológica
16.
Int J Mol Sci ; 24(21)2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37958825

RESUMO

As central nervous system (CNS)-related disorders present an increasing cause of global morbidity, mortality, and high pressure on our healthcare system, there is an urgent need for new insights and treatment options. The endocannabinoid system (ECS) is a critical network of endogenous compounds, receptors, and enzymes that contribute to CNS development and regulation. Given its multifaceted involvement in neurobiology and its significance in various CNS disorders, the ECS as a whole is considered a promising therapeutic target. Despite significant advances in our understanding of the ECS's role in the CNS, its complex architecture and extensive crosstalk with other biological systems present challenges for research and clinical advancements. To bridge these knowledge gaps and unlock the full therapeutic potential of ECS interventions in CNS-related disorders, a plethora of molecular-genetic tools have been developed in recent years. Here, we review some of the most impactful tools for investigating the neurological aspects of the ECS. We first provide a brief introduction to the ECS components, including cannabinoid receptors, endocannabinoids, and metabolic enzymes, emphasizing their complexity. This is followed by an exploration of cutting-edge imaging tools and genetic models aimed at elucidating the roles of these principal ECS components. Special emphasis is placed on their relevance in the context of CNS and its associated disorders.


Assuntos
Endocanabinoides , Endocanabinoides/metabolismo , Receptores de Canabinoides/metabolismo
17.
Int J Mol Sci ; 24(21)2023 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-37958932

RESUMO

Cannabinoid receptors are expressed in human and animal trigeminal sensory neurons; however, the expression in the equine trigeminal ganglion is unknown. Ten trigeminal ganglia from five horses were collected post-mortem from an abattoir. The expression of cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), and the cannabinoid-related receptors like transient receptor potential vanilloid type 1 (TRPV1), peroxisome proliferator-activated receptor gamma (PPARÉ£), and G protein-related receptor 55 (GPR55) in the trigeminal ganglia (TG) of the horse were studied, using immunofluorescence on cryosections and formalin-fixed paraffin-embedded (FFPE) sections. Neurons and glial cells were identified using fluorescent Nissl staining NeuroTrace® and an antibody directed against the glial marker glial fibrillary acidic protein (GFAP), respectively. Macrophages were identified by means of an antibody directed against the macrophages/microglia marker ionized calcium-binding adapter molecule 1 (IBA1). The protein expression of CB1R, CB2R, TRPV1, and PPARÉ£ was found in the majority of TG neurons in both cryosections and FFPE sections. The expression of GPR55 immunoreactivity was mainly detectable in FFPE sections, with expression in the majority of sensory neurons. Some receptors were also observed in glial cells (CB2R, TRPV1, PPARγ, and GPR55) and inflammatory cells (PPARγ and GPR55). These results support further investigation of such receptors in disorders of equine trigeminal neuronal excitability.


Assuntos
PPAR gama , Gânglio Trigeminal , Humanos , Cavalos , Animais , Receptores de Canabinoides/metabolismo , Gânglio Trigeminal/metabolismo , PPAR gama/metabolismo , Neurônios/metabolismo , Neuroglia/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
18.
Biochem Pharmacol ; 218: 115924, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37972874

RESUMO

Cannabinoid CB2 receptor (CB2R) is a class A G protein-coupled receptor (GPCR) involved in a broad spectrum of physiological processes and pathological conditions. For that reason, targeting CB2R might provide therapeutic opportunities in neurodegenerative disorders, neuropathic pain, inflammatory diseases, and cancer. The main components from Cannabis sativa, such as Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), have been therapeutically exploited and synthetically-derived analogs have been generated. One example is cannabidiol-dimethylheptyl (CBD-DMH), which exhibits anti-inflammatory effects. Nevertheless, its pharmacological mechanism of action is not yet fully understood and is hypothesized for multiple targets, including CB2R. The aim of this study was to further investigate the molecular pharmacology of CBD-DMH on CB2R while CBD was taken along as control. These compounds were screened in equilibrium and kinetic radioligand binding studies and various functional assays, including G protein activation, inhibition of cAMP production and ß-arrestin-2 recruitment. In dissociation studies, CBD-DMH allosterically modulated the radioligand binding. Furthermore, CBD-DMH negatively modulated the G protein activation of reference agonists CP55,940, AEA and 2-AG, but not the agonist-induced ß-arrestin-2 recruitment. Nevertheless, CBD-DMH also displayed competitive binding to CB2R and partial agonism on G protein activation, inhibition of cAMP production and ß-arrestin-2 recruitment. CBD did not exhibit such allosteric behavior and only very weakly bound CB2R without activation. This study shows a dual binding mode of CBD-DMH, but not CBD, to CB2R with the suggestion of two different binding sites. Altogether, it encourages further research into this dual mechanism which might provide a new class of molecules targeting CB2R.


Assuntos
Canabidiol , Canabidiol/farmacologia , Receptores de Canabinoides/metabolismo , beta-Arrestina 1/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Dronabinol , Receptor CB1 de Canabinoide/metabolismo , Agonistas de Receptores de Canabinoides
19.
Cells ; 12(22)2023 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-37998380

RESUMO

GPR55 is involved in many physiological and pathological processes. In cancer, GPR55 has been described to show accelerating and decelerating effects in tumor progression resulting from distinct intracellular signaling pathways. GPR55 becomes activated by LPI and various plant-derived, endogenous, and synthetic cannabinoids. Cannabinoids such as THC exerted antitumor effects by inhibiting tumor cell proliferation or inducing apoptosis. Besides its effects through CB1 and CB2 receptors, THC modulates cellular responses among others via GPR55. Previously, we reported a reduction in Ki67-immunoreactive nuclei of human glioblastoma cells after GPR55 activation in general by THC and in particular by LPI. In the present study, we investigated intracellular mechanisms leading to an altered number of Ki67+ nuclei after stimulation of GPR55 by LPI and THC. Pharmacological analyses revealed a strongly involved PLC-IP3 signaling and cell-type-specific differences in Gα-, Gßγ-, RhoA-ROCK, and calcineurin signaling. Furthermore, immunochemical visualization of the calcineurin-dependent transcription factor NFAT revealed an unchanged subcellular localization after THC or LPI treatment. The data underline the cell-type-specific diversity of GPR55-associated signaling pathways in coupling to intracellular G proteins. Furthermore, this diversity might determine the outcome and the individual responsiveness of tumor cells to GPR55 stimulation by cannabin oids.


Assuntos
Canabinoides , Glioblastoma , Humanos , Receptores de Canabinoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Antígeno Ki-67 , Calcineurina
20.
Int J Mol Sci ; 24(22)2023 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-38003619

RESUMO

Both the endocannabinoid system (ECS) and estrogens have significant roles in cardiovascular control processes. Cannabinoid type 1 receptors (CB1Rs) mediate acute vasodilator and hypotensive effects, although their role in cardiovascular pathological conditions is still controversial. Estrogens exert cardiovascular protection in females. We aimed to study the impact of ECS on vascular functions. Experiments were performed on CB1R knockout (CB1R KO) and wild-type (WT) female mice. Plasma estrogen metabolite levels were determined. Abdominal aortas were isolated for myography and histology. Vascular effects of phenylephrine (Phe), angiotensin II, acetylcholine (Ach) and estradiol (E2) were obtained and repeated with inhibitors of nitric oxide synthase (NOS, Nω-nitro-L-arginine) and of cyclooxygenase (COX, indomethacin). Histological stainings (hematoxylin-eosin, resorcin-fuchsin) and immunostainings for endothelial NOS (eNOS), COX-2, estrogen receptors (ER-α, ER-ß) were performed. Conjugated E2 levels were higher in CB1R KO compared to WT mice. Vasorelaxation responses to Ach and E2 were increased in CB1R KO mice, attenuated by NOS-inhibition. COX-inhibition decreased Phe-contractions, while it increased Ach-relaxation in the WT group but not in the CB1R KO. Effects of indomethacin on E2-relaxation in CB1R KO became opposite to that observed in WT. Histology revealed lower intima/media thickness and COX-2 density, higher eNOS and lower ER-ß density in CB1R KO than in WT mice. CB1R KO female mice are characterized by increased vasorelaxation associated with increased utilization of endothelial NO and a decreased impact of constrictor prostanoids. Our results indicate that the absence or inhibition of CB1Rs may have beneficial vascular effects.


Assuntos
Receptores de Canabinoides , Remodelação Vascular , Animais , Feminino , Camundongos , Acetilcolina/metabolismo , Aorta Abdominal/metabolismo , Ciclo-Oxigenase 2/metabolismo , Receptor beta de Estrogênio/metabolismo , Estrogênios/metabolismo , Indometacina/farmacologia , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/metabolismo , Receptores de Canabinoides/metabolismo , Vasodilatação
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