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1.
Physiol Rep ; 11(1): e15565, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36636759

RESUMO

The endocannabinoid system (eCS) plays critical roles in locomotor function and motor development; however, the roles of non-canonical cannabinoid receptor systems such as transient receptor potential (TRP) channels and the Sonic Hedgehog (SHH) signaling pathway in conjunction with the eCS in sensorimotor development remains enigmatic. To investigate the involvement of canonical and non-canonical cannabinoid receptors, TRP channels, and the SHH pathway in the development of sensorimotor function in zebrafish, we treated developing animals with pharmacological inhibitors of the CB1R, CB2R, TRPA1/TRPV1/TRPM8, and a smoothened (SMO) agonist, along with inhibitors of the eCS catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) during the first ~24 h of zebrafish embryogenesis. Locomotor function was examined by assessing touch-evoked escape swimming at 2 days post-fertilization. We report that FAAH inhibition had no effect on swimming while MAGL inhibition using JZL 184 reduced swimming distance and the dual FAAH/MAGL inhibitor JZL 195 impaired swimming distance and mean swimming velocity. The CB1R antagonist AM 251 prevented locomotor deficits caused by eCS perturbation but the CB2R antagonist AM 630 did not. Inhibition of TRPA1/TRPV1/TRPM8 using AMG 9090 rescued the locomotor reductions caused by FAAH/MAGL inhibition, but not by MAGL inhibition alone. The SMO agonist purmorphamine attenuated the effects of JZL 184 and JZL 195 on swimming distance, but not mean velocity. Together, these findings provide one of the first investigations examining the interactions between the eCS and its non-canonical receptor systems in vertebrate motor development.


Assuntos
Endocanabinoides , Canais de Potencial de Receptor Transitório , Animais , Endocanabinoides/farmacologia , Endocanabinoides/metabolismo , Proteínas Hedgehog/metabolismo , Receptores de Canabinoides/metabolismo , Peixe-Zebra/metabolismo , Canais de Potencial de Receptor Transitório/genética , Canais de Potencial de Receptor Transitório/metabolismo , Monoacilglicerol Lipases/metabolismo , Transdução de Sinais , Inibidores Enzimáticos/farmacologia
2.
Int J Mol Sci ; 24(2)2023 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-36674922

RESUMO

A mass spectrometry-based lipidomic investigation of 30 patients with chronic hepatitis C virus (HCV) infection and 30 age- and sex-matched healthy blood donor controls was undertaken. The clustering and complete separation of these two groups was found by both unsupervised and supervised multivariate data analyses. Three patients who had spontaneously cleared the virus and three who were successfully treated with direct-acting antiviral drugs remained within the HCV-positive metabotype, suggesting that the metabolic effects of HCV may be longer-lived. We identified 21 metabolites that were upregulated in plasma and 34 that were downregulated (p < 1 × 10-16 to 0.0002). Eleven members of the endocannabinoidome were elevated, including anandamide and eight fatty acid amides (FAAs). These likely activated the cannabinoid receptor GPR55, which is a pivotal host factor for HCV replication. FAAH1, which catabolizes FAAs, reduced mRNA expression. Four phosphosphingolipids, d16:1, d18:1, d19:1 sphingosine 1-phosphate, and d18:0 sphinganine 1-phosphate, were increased, together with the mRNA expression for their synthetic enzyme SPHK1. Among the most profoundly downregulated plasma lipids were several lysophosphatidylinositols (LPIs) from 3- to 3000-fold. LPIs are required for the synthesis of phosphatidylinositol 4-phosphate (PI4P) pools that are required for HCV replication, and LPIs can also activate the GPR55 receptor. Our plasma lipidomic findings shed new light on the pathobiology of HCV infection and show that a subset of bioactive lipids that may contribute to liver pathology is altered by HCV infection.


Assuntos
Hepatite C Crônica , Hepatite C , Humanos , Hepacivirus/fisiologia , Endocanabinoides , Replicação Viral , Antivirais , RNA Mensageiro
3.
Islets ; 15(1): 1-11, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-36598083

RESUMO

The following review focuses on the scientific studies related to the role of endocannabinoid system (ECS) in pancreatic islet physiology and dysfunction. Different natural or synthetic agonists and antagonists have been suggested as an alternative treatment for diabetes, obesity and metabolic syndrome. Therapeutic use of Cannabis led to the discovery and characterization of the ECS, a signaling complex involved in regulation of various physiological processes, including food intake and metabolism. After the development of different agonists and antagonists, evidence have demonstrated the presence and activity of cannabinoid receptors in several organs and tissues, including pancreatic islets. Insulin and glucagon expression, stimulated secretion, and the development of diabetes and other metabolic disorders have been associated with the activity and modulation of ECS in pancreatic islets. However, according to the animal model and experimental design, either endogenous or pharmacological ligands of cannabinoid receptors have guided to contradictory and paradoxical results that suggest a complex physiological interaction. In consensus, ECS activity modulates insulin and glucagon secretions according to glucose in media; over-stimulation of cannabinoid receptors affects islets negatively, leading to glucose intolerance, meanwhile the treatment with antagonists in diabetic models and humans suggests an improvement in islets function.


Assuntos
Diabetes Mellitus , Ilhotas Pancreáticas , Síndrome Metabólica , Animais , Humanos , Endocanabinoides/metabolismo , Glucagon/metabolismo , Síndrome Metabólica/metabolismo , Ilhotas Pancreáticas/metabolismo , Insulina/metabolismo , Diabetes Mellitus/metabolismo , Receptores de Canabinoides/metabolismo
4.
J Neurodev Disord ; 15(1): 1, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36624400

RESUMO

Multiple lines of evidence suggest a central role for the endocannabinoid system (ECS) in the neuronal development and cognitive function and in the pathogenesis of fragile X syndrome (FXS). This review describes the ECS, its role in the central nervous system, how it is dysregulated in FXS, and the potential role of cannabidiol as a treatment for FXS. FXS is caused by deficiency or absence of the fragile X messenger ribonucleoprotein 1 (FMR1) protein, FMRP, typically due to the presence of >200 cytosine, guanine, guanine sequence repeats leading to methylation of the FMR1 gene promoter. The absence of FMRP, following FMR1 gene-silencing, disrupts ECS signaling, which has been implicated in FXS pathogenesis. The ECS facilitates synaptic homeostasis and plasticity through the cannabinoid receptor 1, CB1, on presynaptic terminals, resulting in feedback inhibition of neuronal signaling. ECS-mediated feedback inhibition and synaptic plasticity are thought to be disrupted in FXS, leading to overstimulation, desensitization, and internalization of presynaptic CB1 receptors. Cannabidiol may help restore synaptic homeostasis by acting as a negative allosteric modulator of CB1, thereby attenuating the receptor overstimulation, desensitization, and internalization. Moreover, cannabidiol affects DNA methylation, serotonin 5HT1A signal transduction, gamma-aminobutyric acid receptor signaling, and dopamine D2 and D3 receptor signaling, which may contribute to beneficial effects in patients with FXS. Consistent with these proposed mechanisms of action of cannabidiol in FXS, in the CONNECT-FX trial the transdermal cannabidiol gel, ZYN002, was associated with improvements in measures of social avoidance, irritability, and social interaction, particularly in patients who are most affected, showing ≥90% methylation of the FMR1 gene.


Assuntos
Canabidiol , Síndrome do Cromossomo X Frágil , Humanos , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Endocanabinoides/metabolismo , Proteína do X Frágil de Retardo Mental/genética
5.
Methods Mol Biol ; 2625: 115-127, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36653638

RESUMO

Endocannabinoids (eCBs) are a family of lipid molecules with important regulatory function in the brain and immune system. The two well-studied eCBs are arachidonic acid derivatives, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG). Currently one of the most important methods for quantitative analysis of eCBs and related lipids from biological matrices is liquid chromatographic separation coupled with tandem mass spectroscopy (LC-MS/MS) owing to its high sensitivity and selectivity, as well as no derivatization procedures needed. Here we describe pretreatment procedures using solid-phase extraction for tissue sampling and an in vivo brain microdialysis approach prior to LC-MS/MS analysis, followed by detailed steps of LC-MS/MS analytic method to demonstrate the potential and application of this method in quantification of eCBs and congeners from various biological matrices.


Assuntos
Endocanabinoides , Espectrometria de Massas em Tandem , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Ácido Araquidônico , Encéfalo
6.
Int J Mol Sci ; 24(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36674424

RESUMO

The regulation and metabolism of the endocannabinoid system has received extensive attention for their potential neuroprotective effect in neurodegenerative diseases such as Alzheimer's disease (AD), which is characterized by amyloid ß (Aß) -induced cell toxicity, inflammation, and oxidative stress. Using in vitro techniques and two cell lines, the mouse hippocampus-derived HT22 cells and Chinese hamster ovary (CHO) cells expressing human cannabinoid receptor type 1 (CB1), we investigated the ability of endocannabinoids to inhibit Aß aggregation and protect cells against Aß toxicity. The present study provides evidence that endocannabinoids N-arachidonoyl ethanol amide (AEA), noladin and O-arachidonoyl ethanolamine (OAE) inhibit Aß42 aggregation. They were able to provide protection against Aß42 induced cytotoxicity via receptor-mediated and non-receptor-mediated mechanisms in CB1-CHO and HT22 cells, respectively. The aggregation kinetic experiments demonstrate the anti-Aß aggregation activity of some endocannabinoids (AEA, noladin). These data demonstrate the potential role and application of endocannabinoids in AD pathology and treatment.


Assuntos
Doença de Alzheimer , Endocanabinoides , Camundongos , Animais , Cricetinae , Humanos , Endocanabinoides/farmacologia , Endocanabinoides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Células CHO , Cricetulus , Doença de Alzheimer/metabolismo
7.
PLoS One ; 18(1): e0279863, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36638082

RESUMO

BACKGROUND: Human amniotic and amniochorionic membranes (AM, ACM) represent the most often used grafts accelerating wound healing. Palmitoylethanolamide, oleoylethanolamide and anandamide are endogenous bioactive lipid molecules, generally referred as N-acylethanolamines. They express analgesic, nociceptive, neuroprotective and anti-inflammatory properties. We assessed the distribution of these lipid mediators in placental tissues, as they could participate on analgesic and wound healing effect of AM/ACM grafts. METHODS: Seven placentas were collected after caesarean delivery and fresh samples of AM, ACM, placental disc, umbilical cord, umbilical serum and vernix caseosa, and decontaminated samples (antibiotic solution BASE 128) of AM and ACM have been prepared. Ultra-high-performance liquid chromatography-tandem mass spectrometry was used for N-acylethanolamines analysis. RESULTS: N-acylethanolamines were present in all studied tissues, palmitoylethanolamide being the most abundant and the anandamide the least. For palmitoylethanolamide the maximum average concentration was detected in AM (350.33 ± 239.26 ng/g), while oleoylethanolamide and anandamide were most abundant in placenta (219.08 ± 79.42 ng/g and 30.06 ± 7.77 ng/g, respectively). Low levels of N-acylethanolamines were found in serum and vernix. A significant increase in the levels of N-acylethanolamines (3.1-3.6-fold, P < 0.001) was observed in AM when the tissues were decontaminated using antibiotic solution. The increase in decontaminated ACM was not statistically significant. CONCLUSIONS: The presence of N-acylethanolamines, particularly palmitoylethanolamide in AM and ACM allows us to propose these lipid mediators as the likely factors responsible for the anti-hyperalgesic, but also anti-inflammatory and neuroprotective, effects of AM/ACM grafts in wound healing treatment. The increase of N-acylethanolamines levels in AM and ACM after tissue decontamination indicates that tissue processing is an important factor in maintaining the analgesic effect.


Assuntos
Endocanabinoides , Placenta , Gravidez , Humanos , Feminino , Alcamidas Poli-Insaturadas , Etanolaminas , Analgésicos
8.
J Med Chem ; 66(1): 235-250, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36542836

RESUMO

Cannabinoid type 2 receptor (CB2R), belonging to the endocannabinoid system, is overexpressed in pathologies characterized by inflammation, and its activation counteracts inflammatory states. Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the degradation of the main endocannabinoid anandamide; thus, the simultaneous CB2R activation and FAAH inhibition may be a synergistic anti-inflammatory strategy. Encouraged by principal component analysis (PCA) data identifying a wide chemical space shared by CB2R and FAAH ligands, we designed a small library of adamantyl-benzamides, as potential dual agents, CB2R agonists, and FAAH inhibitors. The new compounds were tested for their CB2R affinity/selectivity and CB2R and FAAH activity. Derivatives 13, 26, and 27, displaying the best pharmacodynamic profile as CB2R full agonists and FAAH inhibitors, decreased pro-inflammatory and increased anti-inflammatory cytokines production. Molecular docking simulations complemented the experimental findings by providing a molecular rationale behind the observed activities. These multitarget ligands constitute promising anti-inflammatory agents.


Assuntos
Canabinoides , Endocanabinoides/metabolismo , Receptor CB2 de Canabinoide , Simulação de Acoplamento Molecular , Benzamidas/farmacologia , Anti-Inflamatórios/farmacologia , Amidoidrolases , Agonistas de Receptores de Canabinoides , Receptor CB1 de Canabinoide
9.
Addict Biol ; 28(1): e13260, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36577736

RESUMO

Oxycodone is a highly prescribed opioid and its abuse has been rampant. Accumulating evidence shows that the cannabinoid CB1 receptor (CB1R) plays a key role in mediating rewarding effects to opioids. However, the downstream signalling of CB1R induced by oxycodone remains unclear. The neuropeptide oxytocin is well known as a potential remedy for drug addiction. Thus, our study aims to explore the mechanism of oxycodone-induced learning and memory deficits underlying the endocannabinoid system (ECS) and the effect of oxytocin. Rats were intraperitoneally injected with oxycodone once a day for eight consecutive day. Novel object recognition, resident-intruder and Morris Water Maze tests were employed to assess the cognitive, social and spatial memory of the rats after oxycodone withdrawal. The (co-)expression of CB1R, cyclin-dependent kinase 5 (Cdk5), regulatory protein p25, tau and phosphorylated tau was measured 1 day after the last behavioural test. The histopathological staining and synaptic density in the hippocampus were observed as well. We found that oxycodone upregulated the expression of p-GSK3ß, co-expression of p-Cdk5 and p25 through CB1R. This finding was accompanied by elevation of pSer396, pSer404 in the tau, and reduction of the number of neurons, dendritic spines and synaptic density in the hippocampus. Furthermore, i.c.v. treatment with oxytocin ameliorates memory deficits in oxycodone-treated rats through inhibition of the ECS. We propose further studies on the clinical use of this neuropeptide, which may potentially cure drug addiction.


Assuntos
Neuropeptídeos , Ocitocina , Ratos , Animais , Ocitocina/farmacologia , Ocitocina/metabolismo , Endocanabinoides/metabolismo , Oxicodona/farmacologia , Oxicodona/metabolismo , Hipocampo , Analgésicos Opioides/farmacologia , Analgésicos Opioides/metabolismo , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Receptores de Canabinoides/metabolismo , Neuropeptídeos/metabolismo , Receptor CB1 de Canabinoide/metabolismo
10.
Neuropharmacology ; 222: 109304, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36341807

RESUMO

Chronic pain is a persistent, complex condition that contributes to impaired mood, anxiety and emotional problems. Osteoarthritis (OA) is one of the major causes of chronic pain in adults and elderly people. A substantial body of evidence demonstrate that hippocampal neural circuits, especially monoamine dopamine and serotonin levels, contributes to negative affect and avoidance motivation experienced during pain. Current pharmacological strategies for OA patients are unsatisfying and the endocannabinoid system modulation might represent an alternative for the treatment of OA-related pain. In the present study, we used a rat model of osteoarthritis induced by intra-articular injection of sodium monoiodoacetate to assess, 28 days post-induction, the contribution of endocannabinoid system on the possible alteration in pain perception and affective behavior, in LTP and monoamine levels in the lateral entorhinal cortex-dentate gyrus pathway. The results show that OA-related chronic pain induces working memory impairment and depressive-like behavior appearance, diminishes LTP, decreases dopamine levels and increases serotonin levels in the rat dentate gyrus. URB597 administration (i.p., 1 mg/kg) reduces hyperalgesia and mechanical allodynia, improves recognition memory and depressive-live behavior, restores LTP and normalizes monoamine levels in the hippocampus. The effect was observed 60-120 min post-treatment and was blocked by AM251, which proves the action of URB597 via the CB1 receptor. Therefore, our study confirms the role of anandamide in OA-related chronic pain management at the behavioral and hippocampal levels. This article is part of the Special Issue on 'Advances in mechanisms and therapeutic targets relevant to pain'.


Assuntos
Dor Crônica , Osteoartrite , Ratos , Animais , Endocanabinoides , Serotonina , Dopamina , Osteoartrite/tratamento farmacológico , Hipocampo , Aminas , Hiperalgesia
11.
Neuropsychopharmacology ; 48(1): 37-53, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36100658

RESUMO

Endocannabinoids (eCBs) are lipid neuromodulators that suppress neurotransmitter release, reduce postsynaptic excitability, activate astrocyte signaling, and control cellular respiration. Here, we describe canonical and emerging eCB signaling modes and aim to link adaptations in these signaling systems to pathological states. Adaptations in eCB signaling systems have been identified in a variety of biobehavioral and physiological process relevant to neuropsychiatric disease states including stress-related disorders, epilepsy, developmental disorders, obesity, and substance use disorders. These insights have enhanced our understanding of the pathophysiology of neurological and psychiatric disorders and are contributing to the ongoing development of eCB-targeting therapeutics. We suggest future studies aimed at illuminating how adaptations in canonical as well as emerging cellular and synaptic modes of eCB signaling contribute to disease pathophysiology or resilience could further advance these novel treatment approaches.


Assuntos
Endocanabinoides , Sinapses , Humanos , Endocanabinoides/fisiologia , Transmissão Sináptica , Transdução de Sinais
12.
Glia ; 71(1): 36-43, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36408881

RESUMO

In the last decades, astrocytes have emerged as important regulatory cells actively involved in brain function by exchanging signaling with neurons. The endocannabinoid (eCB) signaling is widely present in many brain areas, being crucially involved in multiple brain functions and animal behaviors. The present review presents and discusses current evidence demonstrating that astrocytes sense eCBs released during neuronal activity and subsequently release gliotransmitters that regulate synaptic transmission and plasticity. The eCB signaling to astrocytes and the synaptic regulation mediated by astrocytes activated by eCBs are complex phenomena that exhibit exquisite spatial and temporal properties, a wide variety of downstream signaling mechanisms, and a large diversity of functional synaptic outcomes. Studies investigating this topic have revealed novel regulatory processes of synaptic function, like the lateral regulation of synaptic transmission and the active involvement of astrocytes in the spike-timing dependent plasticity, originally thought to be exclusively mediated by the coincident activity of pre- and postsynaptic neurons, following Hebbian rules for associative learning. Finally, the critical influence of astrocyte-mediated eCB signaling on animal behavior is also discussed.


Assuntos
Endocanabinoides , Plasticidade Neuronal , Animais , Plasticidade Neuronal/fisiologia , Transmissão Sináptica/fisiologia , Transdução de Sinais/fisiologia , Astrócitos/fisiologia
13.
Glia ; 71(1): 44-59, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35822691

RESUMO

The study of the astrocytic contribution to brain functions has been growing in popularity in the neuroscience field. In the last years, and especially since the demonstration of the involvement of astrocytes in synaptic functions, the astrocyte field has revealed multiple functions of these cells that seemed inconceivable not long ago. In parallel, cannabinoid investigation has also identified different ways by which cannabinoids are able to interact with these cells, modify their functions, alter their communication with neurons and impact behavior. In this review, we will describe the expression of different endocannabinoid system members in astrocytes. Moreover, we will relate the latest findings regarding cannabinoid modulation of some of the most relevant astroglial functions, namely calcium (Ca2+ ) dynamics, gliotransmission, metabolism, and inflammation.


Assuntos
Astrócitos , Canabinoides , Astrócitos/metabolismo , Endocanabinoides/metabolismo , Neurônios/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio/fisiologia
14.
Glia ; 71(1): 127-138, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35322459

RESUMO

High-grade gliomas constitute the most frequent and aggressive form of primary brain cancer in adults. These tumors express cannabinoid CB1 and CB2 receptors, as well as other elements of the endocannabinoid system. Accruing preclinical evidence supports that pharmacological activation of cannabinoid receptors located on glioma cells exerts overt anti-tumoral effects by modulating key intracellular signaling pathways. The mechanism of this cannabinoid receptor-evoked anti-tumoral activity in experimental models of glioma is intricate and may involve an inhibition not only of cancer cell survival/proliferation, but also of invasiveness, angiogenesis, and the stem cell-like properties of cancer cells, thereby affecting the complex tumor microenvironment. However, the precise biological role of the endocannabinoid system in the generation and progression of glioma seems very context-dependent and remains largely unknown. Increasing our basic knowledge on how (endo)cannabinoids act on glioma cells could help to optimize experimental cannabinoid-based anti-tumoral therapies, as well as the preliminary clinical testing that is currently underway.


Assuntos
Canabinoides , Glioma , Humanos , Adulto , Endocanabinoides/farmacologia , Glioma/patologia , Receptores de Canabinoides/metabolismo , Receptores de Canabinoides/uso terapêutico , Canabinoides/farmacologia , Transdução de Sinais , Microambiente Tumoral
15.
Glia ; 71(1): 103-126, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35353392

RESUMO

The discovery of cannabinoid receptors as the primary molecular targets of psychotropic cannabinoid Δ9 -tetrahydrocannabinol (Δ9 -THC) in late 1980s paved the way for investigations on the effects of cannabis-based therapeutics in brain pathology. Ever since, a wealth of results obtained from studies on human tissue samples and animal models have highlighted a promising therapeutic potential of cannabinoids and endocannabinoids in a variety of neurological disorders. However, clinical success has been limited and major questions concerning endocannabinoid signaling need to be satisfactorily addressed, particularly with regard to their role as modulators of glial cells in neurodegenerative diseases. Indeed, recent studies have brought into the limelight diverse, often unexpected functions of astrocytes, oligodendrocytes, and microglia in brain injury and disease, thus providing scientific basis for targeting glial cells to treat brain disorders. This Review summarizes the current knowledge on the molecular and cellular hallmarks of endocannabinoid signaling in glial cells and its clinical relevance in neurodegenerative and chronic inflammatory disorders.


Assuntos
Encefalopatias , Canabinoides , Animais , Humanos , Endocanabinoides , Canabinoides/farmacologia , Receptores de Canabinoides/fisiologia , Dronabinol , Microglia
16.
Exp Neurol ; 359: 114232, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36179876

RESUMO

Chemotherapy-induced neuropathic pain is a serious clinical problem and one of the major side effects in cancer treatment. The endocannabinoid system (ECS) plays a crucial role in regulating pain neurotransmission, and changes in the expression of different components of the ECS have been reported in experimental models of persistent pain. In addition, sex differences have been observed in ECS regulation and function. The aim of our study was to evaluate whether administration of oxaliplatin, a neurotoxic antineoplastic agent, induced changes in the expression of ECS components in peripheral and central stations of the pain pathway, and if those changes exhibited sexual dimorphism. Adult male and female rats were injected with oxaliplatin or saline, and mechanical and cold hypersensitivity and allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels corresponding to cannabinoid receptors (CB1, CB2), cannabinoid-related receptors (GPR55, 5HT1A, TRPV1) and to the main enzymes involved in the synthesis (DAGL, DAGL, NAPE-PLD) and degradation (MGL, FAAH) of endocannabinoids were assessed in lumbar dorsal root ganglia (DRGs) and spinal cord by using real time RT-PCR. In addition, the levels of the main endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), were evaluated using commercial ELISA kits. Oxaliplatin administration induced the development of mechanical and cold hypersensitivity and allodynia in male and female animals. Oxaliplatin also induced early and robust changes in the expression of several components of the ECS in DRGs. A marked upregulation of CB1, CB2, 5HT1A and TRPV1 was detected in both sexes. Interestingly, while DAGL mRNA levels remained unchanged, DAGL was downregulated in male and upregulated in female rats. Finally, MGL and NAPE-PLD showed increased levels only in male animals, while FAAH resulted upregulated in both sexes. In parallel, reduced 2-AG and AEA levels were detected in DRGs from male or female rats, respectively. In the lumbar spinal cord, only TRPV1 mRNA levels were found to be upregulated in both sexes. Our results reveal previously unreported changes in the expression of cannabinoid receptors, ligands and enzymes occurring mainly in the peripheral nervous system and displaying certain sexual dimorphism. These changes may contribute to the physiopathology of oxaliplatin-induced neuropathic pain in male and female rats. A better understanding of these dynamic changes will facilitate the development of mechanism- and sex-specific approaches to optimize the use of cannabinoid-based medicines for the treatment of chemotherapy-induced pain.


Assuntos
Antineoplásicos , Canabinoides , Neuralgia , Feminino , Masculino , Ratos , Animais , Endocanabinoides/metabolismo , Endocanabinoides/uso terapêutico , Caracteres Sexuais , Hiperalgesia/metabolismo , Oxaliplatina/toxicidade , Canais de Cátion TRPV/metabolismo , Neuralgia/metabolismo , Receptores de Canabinoides/metabolismo , Antineoplásicos/toxicidade , Antineoplásicos/uso terapêutico , RNA Mensageiro , Modelos Teóricos , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/uso terapêutico , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-36252885

RESUMO

BACKGROUND: The endocannabinoid system (ECS) is increasingly being recognized as key regulatory system coupled with the glucocorticoid system implicated in the pathophysiology of major depressive disorder (MDD). However, prior studies examining the ECS in MDD have been inconclusive, of small sample size or of cross-sectional nature limiting interpretation of causal inferences or time-dependent effects. METHODS: In a prospective community-based cohort study including 128 individuals (women: 108), depressive symptoms (PHQ-9) as well as hair cortisol and endocannabinoids were measured annually over four years (T1-T4). Cortisol, N-arachidonoylethanolamine (AEA), and 2-arachidonoyl-sn-glycerol/1-arachidonoyl-sn-glycerol (2-AG/1-AG) were extracted from 3 cm hair segments reflecting cumulative concentrations of the last three months prior sampling. RESULTS: Cross-sectional group comparisons at baseline revealed reduced AEA and cortisol levels in the group with a positive MDD screening compared to individuals with low depressive symptomatology (both p < .05). Cross-lagged panel models showed that AEA levels at T2 were negatively associated with depressive symptoms at T3 (p < .05). Also, depressive symptoms at T3 were negatively associated with AEA levels at T4 (p < .01). The direction of association was reversed for 2-AG/1-AG, as 2-AG/1-AG levels at T1 were positively associated with depressive symptoms at T2 (p < .01). CONCLUSIONS: While cross-sectional analyses suggest higher depressive symptomatology to be associated with reduced AEA and cortisol release, longitudinal analyses reveal that primarily AEA levels are negatively associated with depressive symptoms. These longitudinal associations elucidate time-dependent relationships between depressive symptomatology and the ECS and further highlight AEA as potential treatment target in MDD.


Assuntos
Transtorno Depressivo Maior , Endocanabinoides , Humanos , Feminino , Hidrocortisona , Depressão/diagnóstico , Estudos Transversais , Estudos Prospectivos , Transtorno Depressivo Maior/diagnóstico , Estudos de Coortes , Glicerol , Alcamidas Poli-Insaturadas , Cabelo
18.
J Med Chem ; 66(1): 538-552, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36516997

RESUMO

Multimodal imaging provides rich biological information, which can be exploited to study drug activity, disease associated phenotypes, and pharmacological responses. Here we show discovery and validation of a new probe targeting the endocannabinoid α/ß-hydrolase domain 6 (ABHD6) enzyme by utilizing positron emission tomography (PET) and matrix-assisted laser desorption/ionization (MALDI) imaging. [18F]JZP-MA-11 as the first PET ligand for in vivo imaging of the ABHD6 is reported and specific uptake in ABHD6-rich peripheral tissues and major brain regions was demonstrated using PET. A proof-of-concept study in nonhuman primate confirmed brain uptake. In vivo pharmacological response upon ABHD6 inhibition was observed by MALDI imaging. These synergistic imaging efforts used to identify biological information cannot be obtained by a single imaging modality and hold promise for improving the understanding of ABHD6-mediated endocannabinoid metabolism in peripheral and central nervous system disorders.


Assuntos
Endocanabinoides , Hidrolases , Animais , Endocanabinoides/metabolismo , Hidrolases/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Monoacilglicerol Lipases , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons
19.
Int J Mol Sci ; 23(24)2022 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-36555739

RESUMO

Early life stress (ELS) increases predisposition to depression. We compared the effects of treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597, and the selective serotonin reuptake inhibitor paroxetine, on ELS-induced depressive-like behavior and the expression of microRNAs (miRs) associated with depression in the medial prefrontal cortex (mPFC), hippocampal CA1 area, lateral habenula and dorsal raphe in rats. We also examined the mRNA expression of serotonergic (htr1a and slc6a4) and endocannabinoid (cnr1, cnr2 and faah) targets in the mPFC following ELS and pharmacological treatment. Adult males and females exposed to the 'Limited Bedding and Nesting' ELS paradigm demonstrated a depressive-like phenotype and late-adolescence URB597 treatment, but not paroxetine, reversed this phenotype. In the mPFC, ELS downregulated miR-16 in males and miR-135a in females and URB597 treatment restored this effect. In ELS females, the increase in cnr2 and decrease in faah mRNAs in the mPFC were reversed by URB597 treatment. We show for the first time that URB597 reversed ELS-induced mPFC downregulation in specific miRs and stress-related behaviors, suggesting a novel mechanism for the beneficial effects of FAAH inhibition. The differential effects of ELS and URB597 on males and females highlight the importance of developing sex-specific treatment approaches.


Assuntos
Amidoidrolases , MicroRNAs , Estresse Psicológico , Animais , Feminino , Masculino , Ratos , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Endocanabinoides/metabolismo , MicroRNAs/genética , Estresse Psicológico/genética , Estresse Psicológico/metabolismo
20.
Neurotox Res ; 40(6): 1690-1706, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36522511

RESUMO

The Endocannabinoid System (ECS, also known as Endocannabinoidome) plays a key role in the function of the Central Nervous System, though the participation of this system on the early development - specifically in neuroprotection and proliferation of nerve cells - has been poorly studied. Here, we collect and describe evidence regarding how cannabinoid receptors CB1R and CB2R regulate several cell markers related to proliferation. While CB1R participates in the modulation of neuronal and glial proliferation, CB2R is involved in the proliferation of glial cells. The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) exert significant effects on nerve cell proliferation. AEA generated during embryogenesis induces major effects on the differentiation of neuronal progenitor cells, whereas 2-AG participates in modulating cell migration events rather than affecting the neural proliferation rate. However, although the ECS has been demonstrated to participate in neuroprotection, more characterization on its role in neuronal and glial proliferation and differentiation is needed, especially in brain areas with recognized high neurogenesis rates. This has encouraged scientists to elucidate and propose specific mechanisms related with these cell proliferation mechanisms to better understand some neurodegenerative disorders such as Parkinson, Huntington and Alzheimer diseases, in which neuronal loss and poor neurogenesis are crucial factors for their onset and progression. In this review, we collect and present recent evidence published pointing to an active role of the ECS in the development and proliferation of nerve cells.


Assuntos
Sistema Nervoso Central , Endocanabinoides , Receptores de Canabinoides/fisiologia , Neurônios , Proliferação de Células
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