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1.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802611

RESUMO

The objective of this work has been to characterize the estrogenic activity of bisphenol-A (BPA) and the adverse effects on the endocannabinoid system (ECS) in modulating germ cell progression. Male offspring exposed to BPA during the foetal-perinatal period at doses below the no-observed-adverse-effect-level were used to investigate the exposure effects in adulthood. Results showed that BPA accumulates specifically in epididymal fat rather than in abdominal fat and targets testicular expression of 3ß-hydroxysteroid dehydrogenase and cytochrome P450 aromatase, thus promoting sustained increase of estrogens and a decrease of testosterone. The exposure to BPA affects the expression levels of some ECS components, namely type-1 (CB1) and type-2 cannabinoid (CB2) receptor and monoacylglycerol-lipase (MAGL). Furthermore, it affects the temporal progression of germ cells reported to be responsive to ECS and promotes epithelial germ cell exfoliation. In particular, it increases the germ cell content (i.e., spermatogonia while reducing spermatocytes and spermatids), accelerates progression of spermatocytes and spermatids, promotes epithelial detachment of round and condensed spermatids and interferes with expression of cell-cell junction genes (i.e., zonula occcludens protein-1, vimentin and ß-catenin). Altogether, our study provides evidence that early exposure to BPA produces in adulthood sustained and site-specific BPA accumulation in epididymal fat, becoming a risk factor for the reproductive endocrine pathways associated to ECS.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/metabolismo , Endocanabinoides/metabolismo , Epididimo/efeitos dos fármacos , Estrogênios/metabolismo , Células Germinativas/efeitos dos fármacos , Fenóis/efeitos adversos , Fenóis/metabolismo , Tecido Adiposo/metabolismo , Animais , Sistema Endócrino/efeitos dos fármacos , Sistema Endócrino/metabolismo , Epididimo/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Células Germinativas/metabolismo , Junções Intercelulares/efeitos dos fármacos , Junções Intercelulares/metabolismo , Masculino , Camundongos , Fatores de Risco , Testosterona/metabolismo
2.
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
3.
Front Immunol ; 12: 631233, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33643316

RESUMO

Coronavirus disease-19 caused by the novel RNA betacoronavirus SARS-CoV2 has first emerged in Wuhan, China in December 2019, and since then developed into a worldwide pandemic with >99 million people afflicted and >2.1 million fatal outcomes as of 24th January 2021. SARS-CoV2 targets the lower respiratory tract system leading to pneumonia with fever, cough, and dyspnea. Most patients develop only mild symptoms. However, a certain percentage develop severe symptoms with dyspnea, hypoxia, and lung involvement which can further progress to a critical stage where respiratory support due to respiratory failure is required. Most of the COVID-19 symptoms are related to hyperinflammation as seen in cytokine release syndrome and it is believed that fatalities are due to a COVID-19 related cytokine storm. Treatments with anti-inflammatory or anti-viral drugs are still in clinical trials or could not reduce mortality. This makes it necessary to develop novel anti-inflammatory therapies. Recently, the therapeutic potential of phytocannabinoids, the unique active compounds of the cannabis plant, has been discovered in the area of immunology. Phytocannabinoids are a group of terpenophenolic compounds which biological functions are conveyed by their interactions with the endocannabinoid system in humans. Here, we explore the anti-inflammatory function of cannabinoids in relation to inflammatory events that happen during severe COVID-19 disease, and how cannabinoids might help to prevent the progression from mild to severe disease.


Assuntos
Anti-Inflamatórios/uso terapêutico , Canabinoides/uso terapêutico , Cannabis/imunologia , Síndrome da Liberação de Citocina/terapia , Fitoterapia , /fisiologia , Endocanabinoides/metabolismo , Humanos , Pandemias
4.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672634

RESUMO

Cannabis has long been used for its medicinal and psychoactive properties. With the relatively new adoption of formal medicinal cannabis regulations worldwide, the study of cannabinoids, both endogenous and exogenous, has similarly flourished in more recent decades. In particular, research investigating the role of cannabinoids in regeneration and neurodevelopment has yielded promising results in vertebrate models. However, regeneration-competent vertebrates are few, whereas a myriad of invertebrate species have been established as superb models for regeneration. As such, this review aims to provide a comprehensive summary of the endocannabinoid system, with a focus on current advances in the area of endocannabinoid system contributions to invertebrate neurodevelopment and regeneration.


Assuntos
Endocanabinoides/metabolismo , Invertebrados/fisiologia , Sistema Nervoso/crescimento & desenvolvimento , Regeneração , Animais , Humanos , Modelos Biológicos , Sinapses/fisiologia
5.
Int J Mol Sci ; 22(4)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668515

RESUMO

Depression, the most prevalent psychiatric disorder in the Western world, is characterized by increased negative affect (i.e., depressed mood, cost value increase) and reduced positive affect (i.e., anhedonia, reward value decrease), fatigue, loss of appetite, and reduced psychomotor activity except for cases of agitative depression. Some forms, such as post-partum depression, have a high risk for suicidal attempts. Recent studies in humans and in animal models relate major depression occurrence and reoccurrence to alterations in dopaminergic activity, in addition to other neurotransmitter systems. Imaging studies detected decreased activity in the brain reward circuits in major depression. Therefore, the location of dopamine receptors in these circuits is relevant for understanding major depression. Interestingly, in cortico-striatal-dopaminergic pathways within the reward and cost circuits, the expression of dopamine and its contribution to reward are modulated by endocannabinoid receptors. These receptors are enriched in the striosomal compartment of striatum that selectively projects to dopaminergic neurons of substantia nigra compacta and is vulnerable to stress. This review aims to show the crosstalk between endocannabinoid and dopamine receptors and their vulnerability to stress in the reward circuits, especially in corticostriatal regions. The implications for novel treatments of major depression are discussed.


Assuntos
Corpo Estriado/metabolismo , Transtorno Depressivo Maior/metabolismo , Neurônios Dopaminérgicos/metabolismo , Endocanabinoides/metabolismo , Parte Compacta da Substância Negra/metabolismo , Corpo Estriado/patologia , Transtorno Depressivo Maior/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/patologia , Humanos , Parte Compacta da Substância Negra/patologia
6.
Int J Mol Sci ; 22(3)2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33530477

RESUMO

In migraine pain, cannabis has a promising analgesic action, which, however, is associated with side psychotropic effects. To overcome these adverse effects of exogenous cannabinoids, we propose migraine pain relief via activation of the endogenous cannabinoid system (ECS) by inhibiting enzymes degrading endocannabinoids. To provide a functional platform for such purpose in the peripheral and central parts of the rat nociceptive system relevant to migraine, we measured by activity-based protein profiling (ABPP) the activity of the main endocannabinoid-hydrolases, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). We found that in trigeminal ganglia, the MAGL activity was nine-fold higher than that of FAAH. MAGL activity exceeded FAAH activity also in DRG, spinal cord and brainstem. However, activities of MAGL and FAAH were comparably high in the cerebellum and cerebral cortex implicated in migraine aura. MAGL and FAAH activities were identified and blocked by the selective and potent inhibitors JJKK-048/KML29 and JZP327A, respectively. The high MAGL activity in trigeminal ganglia implicated in the generation of nociceptive signals suggests this part of ECS as a priority target for blocking peripheral mechanisms of migraine pain. In the CNS, both MAGL and FAAH represent potential targets for attenuation of migraine-related enhanced cortical excitability and pain transmission.


Assuntos
Amidoidrolases/metabolismo , Endocanabinoides/metabolismo , Transtornos de Enxaqueca/etiologia , Transtornos de Enxaqueca/metabolismo , Monoacilglicerol Lipases/metabolismo , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/genética , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Modelos Animais de Doenças , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Hidrólise , Masculino , Monoacilglicerol Lipases/antagonistas & inibidores , Monoacilglicerol Lipases/genética , Nervos Periféricos/metabolismo , Nervos Periféricos/fisiopatologia , Ratos
7.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466734

RESUMO

Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes. The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson's disease, Tourette's syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors. The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood-brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.


Assuntos
Canabinoides/farmacologia , Cannabis/química , Descoberta de Drogas , Compostos Fitoquímicos/farmacologia , Terpenos/farmacologia , Animais , Canabinoides/química , Canabinoides/uso terapêutico , Sinergismo Farmacológico , Endocanabinoides/metabolismo , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Compostos Fitoquímicos/química , Compostos Fitoquímicos/uso terapêutico , Receptores de Canabinoides/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Terpenos/química , Terpenos/uso terapêutico , Síndrome de Tourette/tratamento farmacológico , Síndrome de Tourette/metabolismo
8.
J Med Chem ; 64(1): 123-149, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33379862

RESUMO

The endocannabinoid system (ECS) is involved in a wide range of biological functions and comprises cannabinoid receptors and enzymes responsible for endocannabinoid synthesis and degradation. Over the past 2 decades, significant advances toward developing drugs and positron emission tomography (PET) tracers targeting different components of the ECS have been made. Herein, we summarized the recent development of PET tracers for imaging cannabinoid receptors 1 (CB1R) and 2 (CB2R) as well as the key enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), particularly focusing on PET neuroimaging applications. State-of-the-art PET tracers for the ECS will be reviewed including their chemical design, pharmacological properties, radiolabeling, as well as preclinical and human PET imaging. In addition, this review addresses the current challenges for ECS PET biomarker development and highlights the important role of PET ligands to study disease pathophysiology as well as to facilitate drug discovery.


Assuntos
Endocanabinoides/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Amidoidrolases/antagonistas & inibidores , Animais , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Receptores de Canabinoides/metabolismo
9.
Adv Exp Med Biol ; 1264: 47-65, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33332003

RESUMO

In recent years, an increasing number of investigations has demonstrated the therapeutic potential of molecules targeting the endocannabinoid system. Cannabinoids of endogenous, phytogenic, and synthetic nature have been assessed in a wide variety of disease models ranging from neurological to metabolic disorders. Even though very few compounds of this type have already reached the market, numerous preclinical and clinical studies suggest that cannabinoids are suitable drugs for the clinical management of diverse pathologies.In this chapter, we will provide an overview of the endocannabinoid system under certain physiopathological conditions, with a focus on neurological, oncologic, and metabolic disorders. Cannabinoids evaluated as potential therapeutic agents in experimental models with an emphasis in the most successful chemical entities and their perspectives towards the clinic will be discussed.


Assuntos
Canabinoides/síntese química , Canabinoides/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Canabinoides/metabolismo , Endocanabinoides/metabolismo , Humanos , Doenças Metabólicas/metabolismo , Modelos Biológicos , Neoplasias/metabolismo , Doenças do Sistema Nervoso/metabolismo
10.
Adv Exp Med Biol ; 1264: 111-129, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33332007

RESUMO

The emerging role of the endocannabinoid system (ECS) in the control of symptoms and disease progression in multiple sclerosis (MS) has been highlighted by recent studies. MS is a chronic, immune-mediated, and demyelinating disorder of the central nervous system with no cure so far. It is widely reported that cannabinoids might be used to control MS symptoms and that they also might exert neuroprotective effects and slow down disease progression. The aim of this chapter is to give an overview of the main endogenous and synthetic cannabinoids used for the symptomatic amelioration of MS and their beneficial outcomes, providing new possible perspectives for the treatment of this disease.


Assuntos
Canabinoides/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Endocanabinoides/metabolismo , Humanos , Esclerose Múltipla/metabolismo
11.
Adv Exp Med Biol ; 1264: 131-153, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33332008

RESUMO

With the increasing global use of medical and adult recreational use of cannabis and cannabinoids, this chapter provides overview of evidence from animal and human studies on psychiatric disorders and cannabinoid receptors. We review and present evaluation of the relationship between changes in the ECS and psychiatric disorders. Evidence suggests the existence of a relationship between changes in components of the ECS, and some of the symptoms present in psychiatric disorders. Both CB1Rs and CB2Rs are components of the endocannabinoid system with different cellular and tissue localization patterns that are differentially expressed in the CNS and PNS and are emerging targets for the treatment of number psychiatric disorders. As cannabis preparations are widely used for recreation globally, it is predictable that cannabis use disorders (CUDs) will increase and there is currently no available treatment for CUDs. Although major advances have been reported from cannabinoid and ECS research, there are gaps in scientific knowledge on long-term consequences of cannabis use. Adolescent and cannabis use during pregnancy presents further challenges, and more research will uncover the signaling pathways that couple the gut microbiota with the host ECS. Development of cannabis and cannabinoid nanomedicine for nanotherapy will certainly overcome some of the shortcomings and challenges in medicinal and recreational use of cannabis and cannabinoids. Thus, nanotechnology will allow targeted delivery of cannabinoid formulations with the potential to elevate their use to scientifically validated nanotherapeutic applications as the field of cannabis nanoscience matures.


Assuntos
Canabinoides/metabolismo , Canabinoides/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/metabolismo , Receptores de Canabinoides/metabolismo , Animais , Canabinoides/administração & dosagem , Cannabis/efeitos adversos , Cannabis/metabolismo , Endocanabinoides/metabolismo , Humanos , Nanomedicina
12.
Sci Rep ; 10(1): 22403, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33376241

RESUMO

In their line of duty, Emergency Medical Services (EMS) personnel are exposed to chronically stressful working conditions and recurrent traumatic events, which increase their risk for detrimental health outcomes. Here, we investigated whether this risk is due to altered regulation of the hypothalamus-pituitary-adrenal (HPA) axis and the endocannabinoid system. Therefore, 1 cm hair strands were collected from a cohort of 72 German EMS personnel in order to measure concentrations of cortisol, endocannabinoids [i.e., anandamide (AEA), 2-arachidonoylglycerol (2-AG)], and N-acylethanolamines [i.e., stearoylethanolamide (SEA), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA)]. Rank correlation analyses were conducted to test associations of cortisol, endocannabinoid, and N-acylethanolamine concentrations with the EMS personnel's workload, lifetime trauma exposure, and mental and physical health problems. We found a negative correlation between cortisol and 2-AG concentrations in hair. Higher hair cortisol was associated with higher workload. Reported traumatic stress during childhood and later in life as well as more severe depressive and physical stress symptoms were associated with elevated 2-AG, SEA, OEA, and PEA concentrations. Future longitudinal research needs to address the prospect of tracing biomolecular markers of glucocorticoid, endocannabinoid, and N-acylethanolamine activity as a predicting value of the long-term course of mental and physical well-being.


Assuntos
Serviços Médicos de Emergência , Endocanabinoides/metabolismo , Etanolaminas/metabolismo , Cabelo/metabolismo , Pessoal de Saúde , Hidrocortisona/metabolismo , Estresse Psicológico/metabolismo , Carga de Trabalho , Ferimentos e Lesões/metabolismo , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Nat Commun ; 11(1): 6407, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33335094

RESUMO

Endocannabinoids retrogradely regulate synaptic transmission and their abundance is controlled by the fine balance between endocannabinoid synthesis and degradation. While the common assumption is that "on-demand" release determines endocannabinoid signaling, their rapid degradation is expected to control the temporal profile of endocannabinoid action and may impact neuronal signaling. Here we show that memory formation through fear conditioning selectively accelerates the degradation of endocannabinoids in the cerebellum. Learning induced a lasting increase in GABA release and this was responsible for driving the change in endocannabinoid degradation. Conversely, Gq-DREADD activation of cerebellar Purkinje cells enhanced endocannabinoid signaling and impaired memory consolidation. Our findings identify a previously unappreciated reciprocal interaction between GABA and the endocannabinoid system in which GABA signaling accelerates endocannabinoid degradation, and triggers a form of learning-induced metaplasticity.


Assuntos
Endocanabinoides/metabolismo , Consolidação da Memória/fisiologia , Transmissão Sináptica/fisiologia , Animais , Cerebelo/metabolismo , Condicionamento Clássico , Medo , Masculino , Camundongos Endogâmicos C57BL , Monoacilglicerol Lipases/metabolismo , Células de Purkinje/metabolismo , Células de Renshaw/metabolismo , Ácido gama-Aminobutírico/metabolismo
14.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333772

RESUMO

Neuroinflammation is a physiological response aimed at maintaining the homodynamic balance and providing the body with the fundamental resource of adaptation to endogenous and exogenous stimuli. Although the response is initiated with protective purposes, the effect may be detrimental when not regulated. The physiological control of neuroinflammation is mainly achieved via regulatory mechanisms performed by particular cells of the immune system intimately associated with or within the nervous system and named "non-neuronal cells." In particular, mast cells (within the central nervous system and in the periphery) and microglia (at spinal and supraspinal level) are involved in this control, through a close functional relationship between them and neurons (either centrally, spinal, or peripherally located). Accordingly, neuroinflammation becomes a worsening factor in many disorders whenever the non-neuronal cell supervision is inadequate. It has been shown that the regulation of non-neuronal cells-and therefore the control of neuroinflammation-depends on the local "on demand" synthesis of the endogenous lipid amide Palmitoylethanolamide and related endocannabinoids. When the balance between synthesis and degradation of this bioactive lipid mediator is disrupted in favor of reduced synthesis and/or increased degradation, the behavior of non-neuronal cells may not be appropriately regulated and neuroinflammation exceeds the physiological boundaries. In these conditions, it has been demonstrated that the increase of endogenous Palmitoylethanolamide-either by decreasing its degradation or exogenous administration-is able to keep neuroinflammation within its physiological limits. In this review the large number of studies on the benefits derived from oral administration of micronized and highly bioavailable forms of Palmitoylethanolamide is discussed, with special reference to neuroinflammatory disorders.


Assuntos
Amidas/administração & dosagem , Amidas/metabolismo , Etanolaminas/administração & dosagem , Etanolaminas/metabolismo , Inflamação/dietoterapia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Ácidos Palmíticos/administração & dosagem , Ácidos Palmíticos/metabolismo , Doença de Alzheimer/dietoterapia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Esclerose Amiotrófica Lateral/dietoterapia , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/metabolismo , Animais , Transtorno do Espectro Autista/dietoterapia , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/metabolismo , Endocanabinoides/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Redes e Vias Metabólicas , Esclerose Múltipla/dietoterapia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Doenças do Sistema Nervoso/dietoterapia , Doenças do Sistema Nervoso/metabolismo , Doenças Neurodegenerativas/dietoterapia , Doenças Neurodegenerativas/metabolismo , Dor/dietoterapia , Dor/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo
15.
Adv Exp Med Biol ; 1274: 177-201, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32894511

RESUMO

Cannabis and cannabinoid-based extracts have long been utilized for their perceived therapeutic value, and support for the legalization of cannabis for medicinal purposes continues to increase worldwide. Since the discovery of Δ9-tetrahydrocannabinol (THC) as the primary psychoactive component of cannabis over 50 years ago, substantial effort has been directed toward detection of endogenous mediators of cannabinoid activity. The discovery of anandamide and 2-arachidonoylglycerol as two endogenous lipid mediators of cannabinoid-like effects (endocannabinoids) has inspired exponential growth in our understanding of this essential pathway, as well as the pathological conditions that result from dysregulated endocannabinoid signaling. This review examines current knowledge of the endocannabinoid system including metabolic enzymes involved in biosynthesis and degradation and their receptors, and evaluates potential druggable targets for therapeutic intervention.


Assuntos
Endocanabinoides/metabolismo , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Canabinoides/antagonistas & inibidores , Canabinoides/metabolismo , Cannabis/química , Dronabinol/antagonistas & inibidores , Dronabinol/metabolismo , Endocanabinoides/antagonistas & inibidores , Humanos
16.
Life Sci ; 257: 118109, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32698072

RESUMO

Rheumatoid arthritis is an inflammatory autoimmune disease, characterized by synovial proliferation, destruction to articular cartilage and severe pain. The cannabinoids obtained from Cannabis sativa exhibited their actions via cannabinoid-1 and -2 receptors, which also provides a platform for endocannabinoids to act. The endocannabinoid system comprises endocannabinoid molecules involved in signaling processes, along with G-protein coupled receptors and enzymes associated with ligand biosynthesis, activation and degradation. The action of endocannabinoid system in immune system regulation, via primary CB2 activation, followed by inhibition of production of pro-inflammatory cytokines, auto-antibodies and MMPs, FLSs proliferation and T-cell mediated immune response, are elaborated as potential therapeutic regimes in rheumatoid arthritis. The involvement of endocannabinoid system in immune cells like, B cells, T cells and macrophages, as well as regulatory actions on sensory noniceptors to ameliorate pain is significantly highlighted in the review, elaborating the actions of endocannabinoid signaling in mitigating the disease events. The review also focuses on enhancement of endocannabinoid tone, either by inhibiting the degradation enzymes, like FAAH, MAGL, COX, CytP450, LOX, etc. or by retarding cellular uptake processes. Moreover, the review portrays the optimizing role of endocannabinoid system, in abbreviating the symptoms and complications of rheumatoid arthritis in patients and mitigating inflammation, pain and immune mediated effects significantly.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Endocanabinoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Artrite Reumatoide/metabolismo , Endocanabinoides/antagonistas & inibidores , Humanos , Sistema Imunitário/metabolismo , Inflamação/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo
17.
Sci Rep ; 10(1): 7236, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350298

RESUMO

Emerging evidence points to the role of the endocannabinoid system in long-term stress-induced neural remodeling with studies on stress-induced endocannabinoid dysregulation focusing on cerebral changes that are temporally proximal to stressors. Little is known about temporally distal and sex-specific effects, especially in cerebellum, which is vulnerable to early developmental stress and is dense with cannabinoid receptors. Following limited bedding at postnatal days 2-9, adult (postnatal day 70) cerebellar and hippocampal endocannabinoids, related lipids, and mRNA were assessed, and behavioral performance evaluated. Regional and sex-specific effects were present at baseline and following early-life stress. Limited bedding impaired peripherally-measured basal corticosterone in adult males only. In the CNS, early-life stress (1) decreased 2-arachidonoyl glycerol and arachidonic acid in the cerebellar interpositus nucleus in males only; (2) decreased 2-arachidonoyl glycerol in females only in cerebellar Crus I; and (3) increased dorsal hippocampus prostaglandins in males only. Cerebellar interpositus transcriptomics revealed substantial sex effects, with minimal stress effects. Stress did impair novel object recognition in both sexes and social preference in females. Accordingly, the cerebellar endocannabinoid system exhibits robust sex-specific differences, malleable through early-life stress, suggesting the role of endocannabinoids and stress to sexual differentiation of the brain and cerebellar-related dysfunctions.


Assuntos
Endocanabinoides/metabolismo , Hipocampo , Caracteres Sexuais , Maturidade Sexual , Estresse Psicológico , Animais , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Ratos , Ratos Long-Evans , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia
18.
N Z Med J ; 133(1515): 35-45, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32438375

RESUMO

AIMS: The changing medicolegal climate regarding the medicinal use of cannabinoids in New Zealand will increase the likelihood of patients consulting general practitioners (GPs) about these products. Arthritis is a common medical condition for which cannabis-based products are promoted and used; however, doctors' knowledge about the efficacy and safety of these products in the setting of arthritis may be limited. METHODS: We undertook a rapid review of the medical literature on cannabis-based medicinal products in arthritis. RESULTS: Animal studies have identified endocannabinoid pathways in arthritis that are potentially amenable to interventions. One randomised placebo-controlled trial of Sativex® in adults with rheumatoid arthritis has shown some improvements in pain but not in comparison with a standardised pharmacological treatment regimen. Systematic reviews of cannabis-based products in arthritis have determined that there is currently insufficient evidence to recommend cannabis-based medicines for routine clinical use. There were five ongoing registered clinical trials of cannabis-based products in arthritis, the results of which are yet to be reported. CONCLUSIONS: While animal models have identified possible endocannabinoid pathways in arthritis, there is no clear evidence of benefit in humans or comparative efficacy with current treatments. At this stage, there is little evidence to support GPs prescribing cannabis-based medicinal products for arthritis.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Cannabis , Dor Musculoesquelética/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Animais , Endocanabinoides/metabolismo , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como Assunto
19.
Psychopharmacology (Berl) ; 237(7): 2187-2199, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32399633

RESUMO

RATIONALE: Dysregulation of the endocannabinoid (eCB) system by high doses of Δ9-tetrahydrocannabinol (THC) is hypothesized to generate a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis contributing to cannabinoid hyperemesis syndrome (CHS). OBJECTIVES AND METHODS: Using the conditioned gaping model of nausea, we aimed to determine if pre-treatments that interfere with stress, or an anti-emetic drug, interfere with THC-induced nausea in male rats. The corticotropin-releasing hormone (CRH) antagonist, antalarmin, was given to inhibit the HPA axis during conditioning. Since eCBs inhibit stress, MJN110 (which elevates 2-arachidonylglycerol (2-AG)) and URB597 (which elevates anandamide (AEA)) were also tested. Propranolol (ß-adrenergic antagonist) and WAY-100635 (5-HT1A antagonist) attenuate HPA activation by cannabinoids and, therefore, were assessed. In humans, CHS symptoms are not alleviated by anti-emetic drugs, such as ondansetron (5-HT3 antagonist); however, benzodiazepines are effective. Therefore, ondansetron and chlordiazepoxide were tested. To determine if HPA activation by THC is dose-dependent, corticosterone (CORT) was analyzed from serum of rats treated with 0.0, 0.5, or 10 mg/kg THC. RESULTS: Antalarmin (10 and 20 mg/kg), MJN110 (10 mg/kg), URB597 (0.3 mg/kg), propranolol (2.5 and 5 mg/kg), WAY-100635 (0.5 mg/kg), and chlordiazepoxide (5 mg/kg) interfered with THC-induced conditioned gaping, but the anti-emetic ondansetron (0.1 and 0.01 mg/kg) did not. THC produced significantly higher CORT levels at 10 mg/kg than at 0.0 and 0.5 mg/kg THC. CONCLUSIONS: Treatments that interfere with the stress response also inhibit THC-induced conditioned gaping, but a typical anti-emetic drug does not, supporting the hypothesis that THC-induced nausea, and CHS, is a result of a dysregulated stress response.


Assuntos
Dronabinol/toxicidade , Endocanabinoides/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Náusea/induzido quimicamente , Náusea/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Animais , Antieméticos/farmacologia , Antieméticos/uso terapêutico , Agonistas de Receptores de Canabinoides/toxicidade , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Náusea/tratamento farmacológico , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
20.
J Pharmacol Exp Ther ; 373(3): 353-360, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32241809

RESUMO

Fatty acid amide hydrolase (FAAH) is a key enzyme in the endocannabinoid system. N-(3,4-Dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide ([11C]DFMC) was developed as an irreversible-type positron emission tomography (PET) tracer for FAAH. Here, we attempted to noninvasively estimate rate constant k3 (rate of transfer to the specifically-bound compartment) as a direct index for FAAH in the rat brain. First, the two-tissue compartment model analysis including three parameters [K1-k3, two-tissue compartment model for the irreversible-type radiotracer (2TCMi)] in PET study with [11C]DFMC was conducted, which provided 0.21 ± 0.04 ml·cm-3·min-1 of the net uptake value (Ki), an indirect index for FAAH, in the FAAH-richest region (the cingulate cortex). Subsequently, to noninvasively estimate Ki value, the reference model analysis (Patlak graphical analysis reference model) was tried using a time-activity curve of the spinal cord. In that result, the noninvasive Ki value (KREF) was concisely estimated with high correlation (r > 0.95) to Ki values based on 2TCMi. Using estimated KREF value, we tried to obtain calculated-k3 based on previously defined equations. The calculated k3 was successfully estimated with high correlation (r = 0.95) to direct k3 in 2TCMi. Finally, the dose relationship study using calculated k3 demonstrated that in vivo ED50 value of [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate, a major inhibitor of FAAH, was 66.4 µg/kg in rat brain. In conclusion, we proposed the calculated k3 as an alternative index corresponding to regional FAAH concentrations and suggested that PET with [11C]DFMC enables occupancy study for new pharmaceuticals targeting FAAH. SIGNIFICANCE STATEMENT: In the present study, we proposed calculated k3 as an alternative index corresponding with fatty acid amide hydrolase concentration. By using calculated k3, in vivo ED50 of [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate was successfully estimated to be 66.4 µg/kg for rats. Thus, we demonstrated the pharmacological utility of positron emission tomography with N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide.


Assuntos
Amidoidrolases/metabolismo , Encéfalo/metabolismo , Carbamatos/farmacologia , Radioisótopos de Carbono/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Roedores/metabolismo , Animais , Endocanabinoides/metabolismo , Masculino , Compostos Radiofarmacêuticos/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual/fisiologia
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