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1.
Nutrients ; 13(8)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34445045

RESUMO

In recent years, strong evidence has emerged that exposure to a maternal high-fat diet (HFD) provokes changes in the structure, function, and development of the offspring's brain and may induce several neurodevelopmental and psychiatric illnesses. The aims of this study were to evaluate the effects of a maternal HFD during pregnancy and lactation on depressive-like behavior and Cnr1 gene expression (encoding the CB1 receptor) in brain structures of rat offspring and to investigate the epigenetic mechanism involved in this gene expression. We found that a maternal HFD during pregnancy and lactation induced a depressive-like phenotype at postnatal days (PNDs) 28 and 63. We found that a maternal HFD decreased the Cnr1 mRNA levels in the prefrontal cortex with the increased levels of miR-212-5p and methylation of CpG islands at the Cnr1 promoter and reduced the level of Cnr1 gene expression in the dorsal striatum with an increased level of miR-154-3p in adolescent male offspring. A contrasting effect of a maternal HFD was observed in the hippocampus, where upregulation of Cnr1 gene expression was accompanied by a decrease of miR-154-3p (at PNDs 28 and 63) and miR-212-5p (at PND 63) expression and methylation of CpG islands at the Cnr1 promoter in male offspring. In summary, we showed that a maternal HFD during pregnancy and lactation triggered several epigenetic mechanisms in the brains of rat offspring, which may be related to long-lasting alterations in the next generation and produce behavioral changes in offspring, including a depressive-like phenotype.


Assuntos
Depressão/genética , Dieta Hiperlipídica/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Receptor CB1 de Canabinoide/metabolismo , Animais , Comportamento Animal , Encéfalo/metabolismo , Epigênese Genética , Feminino , Expressão Gênica , Lactação/genética , Masculino , Gravidez , Ratos
2.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360934

RESUMO

The activity of specific populations of neurons in different brain areas makes decisions regarding proper synaptic transmission, the ability to make adaptations in response to different external signals, as well as the triggering of specific regulatory pathways to sustain neural function. The endocannabinoid system (ECS) appears to be a very important, highly expressed, and active system of control in the central nervous system (CNS). Functionally, it allows the cells to respond quickly to processes that occur during synaptic transmission, but can also induce long-term changes. The endocannabinoids (eCBs) belong to a large family of bioactive lipid mediators that includes amides, esters, and ethers of long-chain polyunsaturated fatty acids. They are produced "on demand" from the precursors located in the membranes, exhibit a short half-life, and play a key role as retrograde messengers. eCBs act mainly through two receptors, CB1R and CB2R, which belong to the G-protein coupled receptor superfamily (GPCRs), but can also exert their action via multiple non-receptor pathways. The action of eCBs depends on Ca2+, but eCBs can also regulate downstream Ca2+ signaling. In this short review, we focus on the regulation of neuronal calcium channels by the most effective members of eCBs-2-arachidonoylglycerol (2-AG), anandamide (AEA) and originating from AEA-N-arachidonoylglycine (NAGly), to better understand the contribution of ECS to brain function under physiological conditions.


Assuntos
Encéfalo/metabolismo , Canais de Cálcio/metabolismo , Cálcio/metabolismo , Endocanabinoides/metabolismo , Transmissão Sináptica , Animais , Humanos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Transdução de Sinais
3.
Molecules ; 26(16)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34443679

RESUMO

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a "two-bottle" as well as a "drinking in the dark" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.


Assuntos
Consumo de Bebidas Alcoólicas/patologia , Antagonistas de Receptores de Canabinoides/farmacologia , Endotoxemia/patologia , Etanol/efeitos adversos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Receptor CB1 de Canabinoide/antagonistas & inibidores , Consumo de Bebidas Alcoólicas/sangue , Animais , Ansiedade/sangue , Ansiedade/complicações , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/complicações , Cicloexanóis/administração & dosagem , Teste de Labirinto em Cruz Elevado , Endotoxemia/sangue , Endotoxemia/complicações , Endotoxinas/sangue , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Hipotermia Induzida , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Pirazóis/administração & dosagem , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto/administração & dosagem , Rimonabanto/farmacologia , Estereoisomerismo , Sulfonamidas/administração & dosagem
4.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361066

RESUMO

Ceramides, a class of sphingolipids containing a backbone of sphingoid base, are the most important and effective structural component for the formation of the epidermal permeability barrier. While ceramides comprise approximately 50% of the epidermal lipid content by mass, the content is substantially decreased in certain inflammatory skin diseases, such as atopic dermatitis (AD), causing improper barrier function. It is widely accepted that the endocannabinoid system (ECS) can modulate a number of biological responses in the central nerve system, prior studies revealed that activation of endocannabinoid receptor CB1, a key component of ECS, triggers the generation of ceramides that mediate neuronal cell fate. However, as the impact of ECS on the production of epidermal ceramide has not been studied, we here investigated whether the ECS stimulates the generation of epidermal ceramides in an IL-4-treated in vitro model of skin inflammation using N-palmitoyl serinol (PS), an analog of the endocannabinoid N-palmitoyl ethanolamine. Accordingly, an IL-4-mediated decrease in cellular ceramide levels was significantly stimulated in human epidermal keratinocytes (KC) following PS treatment through both de novo ceramide synthesis- and sphingomyelin hydrolysis-pathways. Importantly, PS selectively increases ceramides with long-chain fatty acids (FAs) (C22-C24), which mainly account for the formation of the epidermal barrier, through activation of ceramide synthase (CerS) 2 and Cer3 in IL-4-mediated inflamed KC. Furthermore, blockade of cannabinoid receptor CB1 activation by AM-251 failed to stimulate the production of total ceramide as well as long-chain ceramides in response to PS. These studies demonstrate that an analog of endocannabinoid, PS, stimulates the generation of specific ceramide species as well as the total amount of ceramides via the endocannabinoid receptor CB1-dependent mechanism, thereby resulting in the enhancement of epidermal permeability barrier function.


Assuntos
Ceramidas/metabolismo , Inflamação/metabolismo , Queratinócitos/metabolismo , Propanolaminas/farmacologia , Propilenoglicóis/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Pele/metabolismo , Células Cultivadas , Humanos , Técnicas In Vitro , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Propanolaminas/química , Propilenoglicóis/química , Pele/citologia , Pele/efeitos dos fármacos
5.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202590

RESUMO

Neuropathic pain is a chronic pain condition persisting past the presence of any noxious stimulus or inflammation. Zerumbone, of the Zingiber zerumbet ginger plant, has exhibited anti-allodynic and antihyperalgesic effects in a neuropathic pain animal model, amongst other pharmacological properties. This study was conducted to further elucidate the mechanisms underlying zerumbone's antineuropathic actions. Research on therapeutic agents involving cannabinoid (CB) and peroxisome proliferator-activated receptors (PPARs) is rising. These receptor systems have shown importance in causing a synergistic effect in suppressing nociceptive processing. Behavioural responses were assessed using the von Frey filament test (mechanical allodynia) and Hargreaves plantar test (thermal hyperalgesia), in chronic constriction injury (CCI) neuropathic pain mice. Antagonists SR141716 (CB1 receptor), SR144528 (CB2 receptor), GW6471 (PPARα receptor) and GW9662 (PPARγ receptor) were pre-administered before the zerumbone treatment. Our findings indicated the involvement of CB1, PPARα and PPARγ in zerumbone's action against mechanical allodynia, whereas only CB1 and PPARα were involved against thermal hyperalgesia. Molecular docking studies also suggest that zerumbone has a comparable and favourable binding affinity against the respective agonist on the CB and PPAR receptors studied. This finding will contribute to advance our knowledge on zerumbone and its significance in treating neuropathic pain.


Assuntos
Neuralgia , PPAR alfa/antagonistas & inibidores , PPAR gama/antagonistas & inibidores , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , Sesquiterpenos/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neuralgia/patologia , PPAR alfa/metabolismo , PPAR gama/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo
6.
Biochemistry (Mosc) ; 86(7): 818-832, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34284706

RESUMO

This review focuses on new aspects of endocannabinoid functions and mechanisms of activity in central and peripheral synapses, different from the general viewpoint that endocannabinoids are retrograde signaling molecules, which inhibit neurotransmitter release by activating specific presynaptic endocannabinoid receptors CB1 and CB2. Biased agonism of the endogenous and synthetic cannabinoids as well as ability of the CB-receptors to couple not only with classical Gi-proteins, but also with Gs- and Gq-proteins and, moreover, with ß-arrestins (thereby triggering additional signaling pathways in synapses) are described here in detail. Examples of noncanonical tonic activity of endocannabinoids and their receptors and their role in synaptic function are also presented. The role of endocannabinoids in short-term and long-term potentiation of neurotransmitter release in central synapses and their facilitating effect on quantal size and other parameters of acetylcholine release in mammalian neuromuscular junctions are highlighted in this review. In conclusion, it is stated that the endocannabinoid system has a wider range of various multidirectional modulating effects (both potentiating and inhibiting) on neurotransmitter release than initially recognized. Re-evaluation of the functions of endocannabinoid system with consideration of its noncanonical features will lead to better understanding of its role in the normal and pathological functioning of the nervous system and other systems of the body, which has an enormous practical value.


Assuntos
Endocanabinoides/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Sinapses/metabolismo , Animais , Humanos , Transdução de Sinais , Sinapses/fisiologia , Transmissão Sináptica
7.
J Nutr Biochem ; 96: 108805, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34147601

RESUMO

Maternal overnutrition negatively impacts the offspring's health leading to an increased risk of developing chronic diseases or metabolic syndrome in adulthood. What we eat affects the endocannabinoid system (eCS) activity, which in turn modulates lipogenesis and fatty acids utilization in hepatic, muscle, and adipose tissues. This study aimed to evaluate the transgenerational effect of maternal obesity on cannabinoid receptor 1 knock-out (CB1 KO) animals in combination with a postnatal obesogenic diet on the development of metabolic disturbances on their offspring. CB1 KO mice were fed a control diet (CD) or a high-fat diet (HFD; 33% more energy from fat) for 3 months. Offspring born to control and obese mothers were also fed with CD or HFD. We observed that pups born to an HFD-fed mother presented higher postnatal weight, lower hepatic fatty acid amide hydrolase activity, and increased blood cholesterol levels when compared to the offspring born to CD-fed mothers. When female mice born to HFD-fed CB1 KO mothers were exposed to an HFD, they gained more weight, presented elevated blood cholesterol levels, and more abdominal adipose tissue accumulation than control-fed adult offspring. The eCS is involved in several reproductive physiological processes. Interestingly, we showed that CB1 KO mice in gestational day 15 presented resistance to LPS-induced deleterious effects on pregnancy outcome, which was overcome when these mice were obese. Our results suggest that an HFD in CB1 receptor-deficient mice contributes to a "nutritional programming" of the offspring resulting in increased susceptibility to metabolic challenges both perinatally and during adulthood.


Assuntos
Lipopolissacarídeos/efeitos adversos , Obesidade Materna/genética , Receptor CB1 de Canabinoide/genética , Animais , Animais Recém-Nascidos , Dieta Hiperlipídica/efeitos adversos , Feminino , Fenômenos Fisiológicos da Nutrição Materna , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Knockout , Obesidade , Obesidade Materna/metabolismo , Gravidez , Resultado da Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptor CB1 de Canabinoide/metabolismo
8.
FASEB J ; 35(5): e21537, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33817834

RESUMO

Cannabidiol (CBD), a phytocannabinoid from the Cannabis sativa plant, exhibits a broad spectrum of potential therapeutic properties for neurodegenerative diseases. An accumulation of amyloid-ß (Aß) protein is one of the most important neuropathology in neurodegenerative diseases like Alzheimer's disease (AD). Data on the effect of CBD on the amelioration of Aß-induced neurite degeneration and its consequences of life and health spans is sparse. This study aimed to investigate the effects of CBD on neurite outgrowth in cells and lifespan and health span in Caenorhabditis elegans (C. elegans). In human SH-SY5Y neuronal cells, CBD prevented neurite lesion induced by Aß1-42 and increased the expression of fatty acid amide hydrolase (FAAH) and cannabinoid receptor 1 (CB1R). Furthermore, CBD both protected the reduction of dendritic spine density and rescued the activity of synaptic Ca2+ /calmodulin-dependent protein kinase II (CaMKII) from Aß1-42 toxicity in primary hippocampal neurons. In C. elegans, we used the transgenic CL2355 strain of C. elegans, which expresses the human Aß peptide throughout the nervous system and found that CBD treatment extended lifespan and improved health span. The neuroprotective effect of CBD was further explored by observing the dopaminergic neurons using transgenic dat-1: GFP strains using the confocal microscope. This study shows that CBD prevents the neurite degeneration induced by Aß, by a mechanism involving CB1R activation, and extends lifespan and improves health span in Aß-overexpressing worms. Our findings support the potential therapeutic approach of CBD for the treatment of AD patients.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Caenorhabditis elegans/crescimento & desenvolvimento , Canabidiol/farmacologia , Longevidade , Neuroblastoma/tratamento farmacológico , Crescimento Neuronal , Receptor CB1 de Canabinoide/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/crescimento & desenvolvimento , Anticonvulsivantes/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores , Fosforilação , Receptor CB1 de Canabinoide/genética , Fator de Transcrição STAT3/genética
9.
Nat Commun ; 12(1): 2153, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846328

RESUMO

The signals in cerebellar Purkinje cells sufficient to instruct motor learning have not been systematically determined. Therefore, we applied optogenetics in mice to autonomously excite Purkinje cells and measured the effect of this activity on plasticity induction and adaptive behavior. Ex vivo, excitation of channelrhodopsin-2-expressing Purkinje cells elicits dendritic Ca2+ transients with high-intensity stimuli initiating dendritic spiking that additionally contributes to the Ca2+ response. Channelrhodopsin-2-evoked Ca2+ transients potentiate co-active parallel fiber synapses; depression occurs when Ca2+ responses were enhanced by dendritic spiking. In vivo, optogenetic Purkinje cell activation drives an adaptive decrease in vestibulo-ocular reflex gain when vestibular stimuli are paired with relatively small-magnitude Purkinje cell Ca2+ responses. In contrast, pairing with large-magnitude Ca2+ responses increases vestibulo-ocular reflex gain. Optogenetically induced plasticity and motor adaptation are dependent on endocannabinoid signaling, indicating engagement of this pathway downstream of Purkinje cell Ca2+ elevation. Our results establish a causal relationship among Purkinje cell Ca2+ signal size, opposite-polarity plasticity induction, and bidirectional motor learning.


Assuntos
Sinalização do Cálcio , Dendritos/metabolismo , Atividade Motora , Células de Purkinje/metabolismo , Potenciais de Ação , Animais , Channelrhodopsins/metabolismo , Endocanabinoides/metabolismo , Camundongos Transgênicos , Plasticidade Neuronal , Optogenética , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Reflexo Vestíbulo-Ocular , Vigília
10.
J Med Chem ; 64(12): 8104-8126, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-33826336

RESUMO

We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the α-position of nitro group generated two diastereomers, the greater potency and efficacy of erythro, (±)-9 vs threo, (±)-10 constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (±)-9 enantiomers, (-)-(S,R)-13 evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(R,S)-14 was a CB1R allosteric agonist biased toward G protein- vs ß-arrestin1/2-dependent signaling. (-)-(S,R)-13 and (+)-(R,S)-14 were devoid of undesirable side effects (triad test), and (+)-(R,S)-14 reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (-)-(S,R)-13 docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-(R,S)-14 preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.


Assuntos
Agonistas de Receptores de Canabinoides/uso terapêutico , Glaucoma/tratamento farmacológico , Indóis/uso terapêutico , Receptor CB1 de Canabinoide/agonistas , Sítio Alostérico , Animais , Células CHO , Agonistas de Receptores de Canabinoides/síntese química , Agonistas de Receptores de Canabinoides/metabolismo , Cricetulus , Células HEK293 , Hipocampo/citologia , Humanos , Indóis/síntese química , Indóis/metabolismo , Pressão Intraocular/efeitos dos fármacos , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neurônios/efeitos dos fármacos , Receptor CB1 de Canabinoide/química , Receptor CB1 de Canabinoide/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
11.
Biomolecules ; 11(4)2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810505

RESUMO

Growing evidence shows that the immune system is critically involved in Alzheimer's disease (AD) pathogenesis and progression. The modulation and targeting of peripheral immune mechanisms are thus promising therapeutic or preventive strategies for AD. Given the critical involvement of the endocannabinoid (eCB) system in modulating immune functions, we investigated the potential role of the main elements of such a system, namely type-1 and type-2 cannabinoid receptors (CB1 and CB2), and fatty acid amide hydrolase (FAAH), in distinct immune cell populations of the peripheral blood of AD patients. We found that, compared to healthy controls, CB1 and CB2 expression was significantly lower in the B-lymphocytes of AD patients. Moreover, we found that CB2 was significantly lower and FAAH was significantly higher in monocytes of the same subjects. In contrast, T-lymphocytes and NK cells did not show any variation in any of these proteins. Of note, monocytic CB2 and FAAH levels significantly correlated with clinical scores. Furthermore, the pharmacological inactivation of FAAH in monocytes and monocyte-derived macrophages obtained from AD patients was able to modulate their immune responses, by reducing production of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-12, and enhancing that of the anti-inflammatory cytokine IL-10. Furthermore, FAAH blockade skewed AD monocyte-derived macrophages towards a more anti-inflammatory and pro-resolving phenotype. Collectively, our findings highlight a central role of FAAH in regulating AD monocytes/macrophages that could be of value in developing novel monocyte-centered therapeutic approaches aimed at promoting a neuroprotective environment.


Assuntos
Doença de Alzheimer/patologia , Amidoidrolases/metabolismo , Macrófagos/metabolismo , Idoso , Amidoidrolases/antagonistas & inibidores , Benzamidas/farmacologia , Carbamatos/farmacologia , Feminino , Humanos , Interleucina-6/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
12.
J Med Chem ; 64(10): 6937-6948, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33887904

RESUMO

The activation of cannabinoid CB1 receptors (CB1R) by Δ9-tetrahydrocannabinol (THC), the main component of Cannabis sativa, induces analgesia. CB1R activation, however, also causes cognitive impairment via the serotonin 5HT2A receptor (5HT2AR), a component of a CB1R-5HT2AR heteromer, posing a serious drawback for cannabinoid therapeutic use. We have shown that peptides reproducing CB1R transmembrane (TM) helices 5 and 6, fused to a cell-penetrating sequence (CPP), can alter the structure of the CB1R-5HT2AR heteromer and avert THC cognitive impairment while preserving analgesia. Here, we report the optimization of these prototypes into drug-like leads by (i) shortening the TM5, TM6, and CPP sequences, without losing the ability to disturb the CB1R-5HT2AR heteromer, and (ii) extensive sequence remodeling to achieve protease resistance and blood-brain barrier penetration. Our efforts have culminated in the identification of an ideal candidate for cannabis-based pain management, an orally active 16-residue peptide preserving THC-induced analgesia.


Assuntos
Analgésicos/química , Cannabis/química , Peptídeos/química , Administração Oral , Sequência de Aminoácidos , Analgésicos/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Canabinoides/química , Canabinoides/farmacologia , Cannabis/metabolismo , Dimerização , Camundongos , Camundongos Endogâmicos ICR , Simulação de Dinâmica Molecular , Dor/tratamento farmacológico , Dor/patologia , Peptídeos/metabolismo , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2A de Serotonina/metabolismo
13.
Molecules ; 26(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33805951

RESUMO

Persistent deficits in social communication and interaction, and restricted, repetitive patterns of behavior, interests or activities, are the core items characterizing autism spectrum disorder (ASD). Strong inflammation states have been reported to be associated with ASD. The endocannabinoid system (ECS) may be involved in ASD pathophysiology. This complex network of lipid signaling pathways comprises arachidonic acid and 2-arachidonoyl glycerol-derived compounds, their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2) and the associated enzymes. Alterations of the ECS have been reported in both the brain and the immune system of ASD subjects. ASD children show low EC tone as indicated by low blood levels of endocannabinoids. Acetaminophen use has been reported to be associated with an increased risk of ASD. This drug can act through the ECS to produce analgesia. It may be that acetaminophen use in children increases the risk for ASD by interfering with the ECS.This mini-review article summarizes the current knowledge on this topic.


Assuntos
Acetaminofen/efeitos adversos , Transtorno do Espectro Autista , Canabinoides/uso terapêutico , Endocanabinoides/metabolismo , Acetaminofen/uso terapêutico , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/patologia , Humanos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Life Sci ; 276: 119407, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794254

RESUMO

AIMS: The aim of the study was to investigate the interaction between cannabinoid CB1/CB2 and lysophosphatidic acid (LPA) receptors in controlling neuronal signaling and fate. METHODS: HT22 hippocampal cells were treated with different cannabinoid and LPA receptor agonists and antagonists. Western blot and immunofluorescence microscopy were used to study intracellular signaling and the expression of apoptotic markers. Cell viability was determined by a luminescence assay. KEY FINDINGS: Cannabinoid agonists induced activation of both ERK1/2 and p38 MAP kinases. The effects of the CB1/CB2 receptor agonist HU210 were antagonized by the CB1 antagonist rimonabant, whereas the responses to the CB2 agonist JWH133 were blocked by the CB2 antagonist SR144528. HU210 reduced the apoptotic cell death induced by the pro-inflammatory cytokine TNF-α, whereas JWH133 enhanced the cytokine cytotoxicity. Blockade of ERK1/2 and p38 MAPK activation abrogated the HU210 pro-survival and the JWH133 pro-apoptotic effects, respectively. HU210 and the endocannabinoid anandamide, but not JWH133, potentiated ERK1/2 stimulation by LPA and the tricyclic antidepressant amitriptyline acting through the LPA1 receptor. HU210 enhanced amitriptyline-stimulated CREB phosphorylation and protection against TNF-α-induced apoptosis, whereas JWH133 had no effect. ERK1/2 stimulation by either HU210 or amitriptyline was dependent on fibroblast growth factor receptor (FGF-R) kinase activity and the combination of the two stimulants induced FGF-R phosphorylation. Moreover, the CB1 receptor was found to co-immunoprecipitate with the LPA1 receptor. CONCLUSIONS: In HT22 hippocampal cells CB1 and CB2 receptors differentially regulate TNF-α-induced apoptosis and CB1 receptors positively interact with amitriptyline-stimulated LPA1 in promoting FGF-R-mediated ERK1/2 signaling and neuroprotection.


Assuntos
Apoptose , Agonistas de Receptores de Canabinoides/farmacologia , Hipocampo/patologia , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Inibidores da Captação Adrenérgica/farmacologia , Amitriptilina/farmacologia , Animais , Sobrevivência Celular , Células Cultivadas , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Receptores de Ácidos Lisofosfatídicos/genética , Transdução de Sinais
15.
Molecules ; 26(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917187

RESUMO

Cannabinoids comprise different classes of compounds, which aroused interest in recent years because of their several pharmacological properties. Such properties include analgesic activity, bodyweight reduction, the antiemetic effect, the reduction of intraocular pressure and many others, which appear correlated to the affinity of cannabinoids towards CB1 and/or CB2 receptors. Within the search aiming to identify novel chemical scaffolds for cannabinoid receptor interaction, the CB1 antagonist/inverse agonist pyrazole-based derivative rimonabant has been modified, giving rise to several tricyclic pyrazole-based compounds, most of which endowed of high affinity and selectivity for CB1 or CB2 receptors. The aim of this review is to present the synthesis and summarize the SAR study of such tricyclic pyrazole-based compounds, evidencing, for some derivatives, their potential in the treatment of neuropathic pain, obesity or in the management of glaucoma.


Assuntos
Pirazóis/química , Receptor CB1 de Canabinoide/química , Receptor CB2 de Canabinoide/química , Canabinoides/química , Estrutura Molecular , Ligação Proteica , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade
16.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803075

RESUMO

Methamphetamine is, worldwide, one of the most consumed drugs of abuse. One important side effect is neurodegeneration leading to a decrease in life expectancy. The aim of this paper was to check whether the drug affects one of the receptors involved in neurodegeneration/neuroprotection events, namely the adenosine A2A receptor (A2AR). First, we noticed that methamphetamine does not affect A2A functionality if the receptor is expressed in a heterologous system. However, A2AR becomes sensitive to the drug upon complexes formation with the cannabinoid CB1 receptor (CB1R) and the sigma 1 receptor (σ1R). Signaling via both adenosine A2AR and cannabinoid CB1R was affected by methamphetamine in cells co-expressing the two receptors. In striatal primary cultures, the A2AR-CB1R heteromer complex was detected and methamphetamine not only altered its expression but completely blocked the A2AR- and the CB1R-mediated activation of the mitogen activated protein kinase (MAPK) pathway. In conclusion, methamphetamine, with the participation of σ1R, alters the expression and function of two interacting receptors, A2AR, which is a therapeutic target for neuroprotection, and CB1R, which is the most abundant G protein-coupled receptor (GPCR) in the brain.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Corpo Estriado/metabolismo , Metanfetamina/farmacologia , Neurônios/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptores sigma/metabolismo , Animais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos
17.
Molecules ; 26(9)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922473

RESUMO

The CB1 cannabinoid receptor (CB1R) contains one of the longest N termini among class A G protein-coupled receptors. Mutagenesis studies suggest that the allosteric binding site of cannabidiol (CBD) involves residues from the N terminal domain. In order to study the allosteric binding of CBD to CB1R we modeled the whole N-terminus of this receptor using the replica exchange molecular dynamics with solute tempering (REST2) approach. Then, the obtained structures of CB1R with the N terminus were used for ligand docking. A natural cannabinoid receptor agonist, Δ9-THC, was docked to the orthosteric site and a negative allosteric modulator, CBD, to the allosteric site positioned between extracellular ends of helices TM1 and TM2. The molecular dynamics simulations were then performed for CB1R with ligands: (i) CBD together with THC, and (ii) THC-only. Analyses of the differences in the residue-residue interaction patterns between those two cases allowed us to elucidate the allosteric network responsible for the modulation of the CB1R by CBD. In addition, we identified the changes in the orthosteric binding mode of Δ9-THC, as well as the changes in its binding energy, caused by the CBD allosteric binding. We have also found that the presence of a complete N-terminal domain is essential for a stable binding of CBD in the allosteric site of CB1R as well as for the allosteric-orthosteric coupling mechanism.


Assuntos
Canabidiol/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Regulação Alostérica/fisiologia , Sítio Alostérico , Animais , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica , Estrutura Secundária de Proteína , Receptor CB1 de Canabinoide/química
18.
FASEB J ; 35(4): e21232, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33715173

RESUMO

Obesity is associated with chronic inflammation in insulin-sensitive tissues, including liver and adipose tissue, and causes hormonal/metabolic complications, such as insulin resistance. There is growing evidence that peripheral cannabinoid-type 1 receptor (CB1R) is a crucial participant in obesity-induced pro-inflammatory responses in insulin-target tissues, and its selective targeting could be a novel therapeutic strategy to break the link between insulin resistance and metabolic inflammation. In this review, we introduce the role of peripheral CB1R in metabolic inflammation and as a mediator of hormonal/metabolic complications that underlie metabolic syndrome, including fatty liver, insulin resistance, and dyslipidemia. We also discuss the therapeutic potential of second- and third-generation peripherally restricted CB1R antagonists for treating obesity-induced metabolic inflammation without eliciting central CB1R-mediated neurobehavioral effects, predictive of neuropsychiatric side effects, in humans.


Assuntos
Obesidade/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Obesidade/complicações , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/genética
19.
Neuron ; 109(9): 1513-1526.e11, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33770505

RESUMO

Recent advances in neuroscience have positioned brain circuits as key units in controlling behavior, implying that their positive or negative modulation necessarily leads to specific behavioral outcomes. However, emerging evidence suggests that the activation or inhibition of specific brain circuits can actually produce multimodal behavioral outcomes. This study shows that activation of a receptor at different subcellular locations in the same neuronal circuit can determine distinct behaviors. Pharmacological activation of type 1 cannabinoid (CB1) receptors in the striatonigral circuit elicits both antinociception and catalepsy in mice. The decrease in nociception depends on the activation of plasma membrane-residing CB1 receptors (pmCB1), leading to the inhibition of cytosolic PKA activity and substance P release. By contrast, mitochondrial-associated CB1 receptors (mtCB1) located at the same terminals mediate cannabinoid-induced catalepsy through the decrease in intra-mitochondrial PKA-dependent cellular respiration and synaptic transmission. Thus, subcellular-specific CB1 receptor signaling within striatonigral circuits determines multimodal control of behavior.


Assuntos
Encéfalo/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais/fisiologia , Transmissão Sináptica/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Catalepsia/induzido quimicamente , Membrana Celular/metabolismo , Células HEK293 , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
20.
Mol Cell Biochem ; 476(7): 2753-2775, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33713246

RESUMO

Anandamide is an endocannabinoid derived from arachidonic acid-containing membrane lipids and has numerous biological functions. Its effects are primarily mediated by the cannabinoid receptors CB1 and CB2, and the vanilloid TRPV1 receptor. Anandamide is known to be involved in sleeping and eating patterns as well as pleasure enhancement and pain relief. This manuscript provides a review of anandamide synthesis, degradation, and storage and hence the homeostasis of the anandamide signaling system.


Assuntos
Ácidos Araquidônicos , Endocanabinoides , Alcamidas Poli-Insaturadas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Ácidos Araquidônicos/farmacocinética , Ácidos Araquidônicos/uso terapêutico , Endocanabinoides/farmacocinética , Endocanabinoides/uso terapêutico , Humanos , Alcamidas Poli-Insaturadas/farmacocinética , Alcamidas Poli-Insaturadas/uso terapêutico
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