ABSTRACT
The endogenous cannabinoid system (ECS) of the brain plays an important role in the molecular pathogenesis of Parkinson's disease (PD). It is involved in the formation of numerous clinical manifestations of the disease by regulating the level of endogenous cannabinoids and changing the activation of cannabinoid receptors (CBRs). Therefore, ECS modulation with new drugs specifically designed for this purpose may be a promising strategy in the treatment of PD. However, fine regulation of the ECS is quite a complex task due to the functional diversity of CBRs in the basal ganglia and other parts of the central nervous system. In this review, the effects of ECS modulators in various experimental models of PD in vivo and in vitro, as well as in patients with PD, are analyzed. Prospects for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD are presented.
Subject(s)
Parkinson Disease , Receptors, Cannabinoid , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Humans , Animals , Receptors, Cannabinoid/metabolism , Endocannabinoids/metabolism , Cannabinoids/therapeutic use , Cannabinoids/pharmacology , Cannabinoids/metabolismABSTRACT
2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid (EC), acting as a full agonist at both CB1 and CB2 cannabinoid receptors. It is synthesized on demand in postsynaptic membranes through the sequential action of phosphoinositide-specific phospholipase Cß1 (PLCß1) and diacylglycerol lipase α (DAGLα), contributing to retrograde signaling upon interaction with presynaptic CB1. However, 2-AG production might also involve various combinations of PLC and DAGL isoforms, as well as additional intracellular pathways implying other enzymes and substrates. Three other alternative pathways of 2-AG synthesis rest on the extracellular cleavage of 2-arachidonoyl-lysophospholipids by three different hydrolases: glycerophosphodiesterase 3 (GDE3), lipid phosphate phosphatases (LPPs), and two members of ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPP6-7). We propose the names of AlterAG-1, -2, and -3 for three pathways sharing an ectocellular localization, allowing them to convert extracellular lysophospholipid mediators into 2-AG, thus inducing typical signaling switches between various G-protein-coupled receptors (GPCRs). This implies the critical importance of the regioisomerism of both lysophospholipid (LPLs) and 2-AG, which is the object of deep analysis within this review. The precise functional roles of AlterAGs are still poorly understood and will require gene invalidation approaches, knowing that both 2-AG and its related lysophospholipids are involved in numerous aspects of physiology and pathology, including cancer, inflammation, immune defenses, obesity, bone development, neurodegeneration, or psychiatric disorders.
Subject(s)
Arachidonic Acids , Endocannabinoids , Glycerides , Lysophospholipids , Signal Transduction , Endocannabinoids/metabolism , Glycerides/metabolism , Lysophospholipids/metabolism , Humans , Arachidonic Acids/metabolism , Animals , Phosphoric Diester Hydrolases/metabolismABSTRACT
The synthesis of some N-(3-acyloxyacyl)glycines, an interesting class of bioactive gut microbiota metabolites, is described. This procedure involves seven reaction steps using the commercially available Meldrum's acid to obtain highly pure products, in normal or deuterated form. The key point of the synthetic strategy was the use of commendamide t-butyl ester as a synthetic intermediate, a choice that allowed the removal of the protecting group at the end of the synthetic procedure without degrading of the other ester bond present in the molecule. The developed synthetic sequence is particularly simple, uses readily available reagents and involves a limited number of purifications by chromatographic column, with a reduction in the volume of solvent and energy used.
Subject(s)
Endocannabinoids , Gastrointestinal Microbiome , Endocannabinoids/metabolism , Endocannabinoids/chemistry , Humans , Molecular StructureABSTRACT
Synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), is an essential phenomenon in memory formation as well as maintenance along with many other cognitive functions, such as those needed for coping with external stimuli. Synaptic plasticity consists of gradual changes in the biochemistry and morphology of pre- and postsynaptic neurons, particularly in the hippocampus. Consuming marijuana as a primary source of exocannabinoids immediately impairs attention and working memory-related tasks. Evidence regarding the effects of cannabinoids on LTP and memory is contradictory. While cannabinoids can affect a variety of specific cannabinoid receptors (CBRs) and nonspecific receptors throughout the body and brain, they exert miscellaneous systemic and local cerebral effects. Given the increasing use of cannabis, mainly among the young population, plus its potential adverse long-term effects on learning and memory processes, it could be a future global health challenge. Indeed, the impact of cannabinoids on memory is multifactorial and depends on the dosage, timing, formula, and route of consumption, plus the background complex interaction of the endocannabinoids system with other cerebral networks. Herein, we review how exogenously administrated organic cannabinoids, CBRs agonists or antagonists, and endocannabinoids can affect LTP and synaptic plasticity through various receptors in interaction with other cerebral pathways and primary neurotransmitters.
Subject(s)
Cannabinoids , Long-Term Potentiation , Memory , Neuronal Plasticity , Cannabinoids/pharmacology , Cannabinoids/metabolism , Humans , Neuronal Plasticity/drug effects , Animals , Long-Term Potentiation/drug effects , Memory/drug effects , Endocannabinoids/metabolism , Endocannabinoids/pharmacology , Receptors, Cannabinoid/metabolism , Long-Term Synaptic Depression/drug effects , Hippocampus/metabolism , Hippocampus/drug effectsABSTRACT
Endometriosis (EM), characterized by the presence of endometrial-like tissue outside the uterus, is the leading cause of chronic pelvic pain and infertility in females of reproductive age. Despite its high prevalence, the molecular mechanisms underlying EM pathogenesis remain poorly understood. The endocannabinoid system (ECS) is known to influence several cardinal features of this complex disease including pain, vascularization, and overall lesion survival, but the exact mechanisms are not known. Utilizing CNR1 knockout (k/o), CNR2 k/o, and wild-type (WT) mouse models of EM, we reveal contributions of ECS and these receptors in disease initiation, progression, and immune modulation. Particularly, we identified EM-specific T cell dysfunction in the CNR2 k/o mouse model of EM. We also demonstrate the impact of decidualization-induced changes on ECS components, and the unique disease-associated transcriptional landscape of ECS components in EM. Imaging mass cytometry (IMC) analysis revealed distinct features of the microenvironment between CNR1, CNR2, and WT genotypes in the presence or absence of decidualization. This study, for the first time, provides an in-depth analysis of the involvement of the ECS in EM pathogenesis and lays the foundation for the development of novel therapeutic interventions to alleviate the burden of this debilitating condition.
Subject(s)
Endocannabinoids , Endometriosis , Mice, Knockout , Receptor, Cannabinoid, CB1 , Receptor, Cannabinoid, CB2 , Endometriosis/genetics , Endometriosis/metabolism , Endometriosis/pathology , Female , Animals , Endocannabinoids/metabolism , Mice , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB1/genetics , Receptor, Cannabinoid, CB2/genetics , Receptor, Cannabinoid, CB2/metabolism , Disease Models, AnimalABSTRACT
The endocannabinoid system is composed by a complex and ubiquitous network of endogenous lipid ligands, enzymes for their synthesis and degradation, and receptors, which can also be stimulated by exogenous compounds, such as those derived from the Cannabis sativa. Cannabis and its bioactive compounds, including cannabinoids and non-cannabinoids, have been extensively studied in different conditions. Recent data have shown that the endocannabinoid system is responsible for maintaining the homeostasis of various skin functions such as proliferation, differentiation and release of inflammatory mediators. Because of their role in regulating these key processes, cannabinoids have been studied for the treatment of skin cancers and melanoma; their anti-tumour effects regulate skin cancer progression and are mainly related to the inhibition of tumour growth, proliferation, invasion and angiogenesis, through apoptosis and autophagy induction. This review aims at summarising the current field of research on the potential uses of cannabinoids in the melanoma field.
Subject(s)
Cannabinoids , Melanoma , Skin Neoplasms , Humans , Cannabinoids/therapeutic use , Cannabinoids/pharmacology , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Endocannabinoids/metabolism , Endocannabinoids/therapeutic use , Animals , Apoptosis/drug effectsABSTRACT
The addictive use of nicotine contained in tobacco is associated with stressor-like emotional and cognitive effects such as anxiety and working memory impairment, and the involvement of epigenetic mechanisms such as histone acetylation has recently been reported. Although the precise nature of behavioural plasticity remains unclear, both anxiogenic- and working memory impairment-like effects were observed in the present experimental model of mice treated with repeated subcutaneous nicotine and/or immobilization stress, and these effects were commonly attenuated by the histone deacetylase (HDAC) inhibitors that induce histone acetylation. Such HDAC inhibitor-induced resilience was mimicked by ligands for the endocannabinoid (ECB) system, a neurotransmitter system that is closely associated with nicotine-induced addiction-related behaviours: the anxiogenic-like effects were mitigated by the cannabinoid type 1 (CB1) agonist arachidonylcyclopropylamide (ACPA), whereas the working memory impairment-like effects were mitigated by the CB1 antagonist SR 141716A. Moreover, the effects of the HDAC inhibitors were also mimicked by ligands for the endovanilloid (transient receptor potential vanilloid 1 [TRPV1]) system, a system that shares common characteristics with the ECB system: the anxiogenic-like effects were mitigated by the TRPV1 antagonist capsazepine, whereas the working memory impairment-like effects were mitigated by the TRPV1 agonist olvanil. Notably, the HDAC inhibitor-induced anxiolytic-like effects were attenuated by SR 141716A, which were further counteracted by capsazepine, whereas the working memory improvement-like effects were attenuated by capsazepine, which were further counteracted by SR 141716A. These results suggest the contribution of interrelated control of the ECB/TRPV1 systems and epigenetic processes such as histone acetylation to novel therapeutic approaches.
Subject(s)
Anxiety , Endocannabinoids , Epigenesis, Genetic , Memory, Short-Term , Nicotine , Stress, Psychological , TRPV Cation Channels , Animals , TRPV Cation Channels/drug effects , Nicotine/pharmacology , Mice , Memory, Short-Term/drug effects , Endocannabinoids/metabolism , Male , Epigenesis, Genetic/drug effects , Histone Deacetylase Inhibitors/pharmacology , Receptor, Cannabinoid, CB1/drug effects , Memory Disorders/chemically induced , Capsaicin/pharmacology , Capsaicin/analogs & derivatives , Disease Models, Animal , Rimonabant/pharmacology , Nicotinic Agonists/pharmacology , Piperidines/pharmacologyABSTRACT
BACKGROUND: Despite extensive studies on the neurobiological correlates of traumatic brain injury (TBI), little is known about its molecular determinants on long-term consequences, such as dementia and Alzheimer's disease (AD). METHODS: Here, we carried out behavioural studies and an extensive biomolecular analysis, including inflammatory cytokines, gene expression and the combination of LC-HRMS and MALDI-MS Imaging to elucidate the targeted metabolomics and lipidomics spatiotemporal alterations of brains from wild-type and APP-SWE mice, a genetic model of AD, at the presymptomatic stage, subjected to mild TBI. RESULTS: We found that brain injury does not affect cognitive performance in APP-SWE mice. However, we detected an increase of key hallmarks of AD, including Aß1-42 levels and BACE1 expression, in the cortices of traumatized transgenic mice. Moreover, significant changes in the expanded endocannabinoid (eCB) system, or endocannabinoidome (eCBome), occurred, including increased levels of the endocannabinoid 2-AG in APP-SWE mice in both the cortex and hippocampus, and N-acylserotonins, detected for the first time in the brain. The gene expression of enzymes for the biosynthesis and inactivation of eCBs and eCB-like mediators, and some of their main molecular targets, also underwent significant changes. We also identified the formation of heteromers between cannabinoid 1 (CB1) and serotonergic 2A (5HT2A) receptors, whose levels increased in the cortex of APP-SWE mTBI mice, possibly contributing to the exacerbated pathophysiology of AD induced by the trauma. CONCLUSIONS: Mild TBI induces biochemical changes in AD genetically predisposed mice and the eCBome may play a role in the pathogenetic link between brain injury and neurodegenerative disorders also by interacting with the serotonergic system.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Endocannabinoids , Mice, Transgenic , Animals , Alzheimer Disease/metabolism , Alzheimer Disease/genetics , Mice , Endocannabinoids/metabolism , Cognitive Dysfunction/metabolism , Serotonin/metabolism , Biomarkers/metabolism , Male , Brain Concussion/metabolism , Disease Models, Animal , Mice, Inbred C57BL , Brain/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Prodromal Symptoms , Amyloid beta-Peptides/metabolismABSTRACT
The emergence of inflammatory diseases is a heavy burden on modern societies. Cannabis has been used for several millennia to treat inflammatory disorders such as rheumatism or gout. Since the characterization of cannabinoid receptors, CB1 and CB2, the potential of cannabinoid pharmacotherapy in inflammatory conditions has received great interest. Several studies have identified the importance of these receptors in immune cell migration and in the production of inflammatory mediators. As the presence of the CB2 receptor was documented to be more predominant in immune cells, several pharmacological agonists and antagonists have been designed to treat inflammation. To better define the potential of the CB2 receptor, three online databases, PubMed, Google Scholar and clinicaltrial.gov, were searched without language restriction. The full texts of articles presenting data on the endocannabinoid system, the CB2 receptor and its role in modulating inflammation in vitro, in animal models and in the context of clinical trials were reviewed. Finally, we discuss the clinical potential of the latest cannabinoid-based therapies in inflammatory diseases.
Subject(s)
Inflammation , Receptor, Cannabinoid, CB2 , Humans , Receptor, Cannabinoid, CB2/metabolism , Receptor, Cannabinoid, CB2/agonists , Inflammation/metabolism , Inflammation/drug therapy , Animals , Cannabinoids/therapeutic use , Cannabinoids/pharmacology , Endocannabinoids/metabolism , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Cannabinoid Receptor Agonists/pharmacology , Cannabinoid Receptor Agonists/therapeutic useABSTRACT
The endocannabinoid system, known for its regulatory role in various physiological processes, relies on the activities of several hydrolytic enzymes, such as fatty acid amide hydrolase (FAAH), N-acylethanolamine-hydrolyzing acid amidase (NAAA), monoacylglycerol lipase (MAGL), and α/ß-hydrolase domains 6 (ABHD6) and 12 (ABHD12), to maintain homeostasis. Accurate measurement of these enzymes' activities is crucial for understanding their function and for the development of potential therapeutic agents. Fluorometric assays, which offer high sensitivity, specificity, and real-time monitoring capabilities, have become essential tools in enzymatic studies. This review provides a comprehensive overview of the principles behind these assays, the various substrates and fluorophores used, and advances in assay techniques used not only for the determination of the kinetic mechanisms of enzyme reactions but also for setting up kinetic assays for the high-throughput screening of each critical enzyme involved in endocannabinoid degradation. Through this comprehensive review, we aim to highlight the strengths and limitations of current fluorometric assays and suggest future directions for improving the measurement of enzyme activity in the endocannabinoid system.
Subject(s)
Amidohydrolases , Endocannabinoids , Enzyme Assays , Endocannabinoids/metabolism , Humans , Enzyme Assays/methods , Amidohydrolases/metabolism , Amidohydrolases/antagonists & inhibitors , Hydrolysis , Monoacylglycerol Lipases/metabolism , Monoacylglycerol Lipases/antagonists & inhibitors , Animals , Fluorometry/methods , Fluorescence , Kinetics , Fluorescent Dyes/chemistry , Enzyme Inhibitors/pharmacologyABSTRACT
Linoleic acid (LA) is required for neuronal development. We have previously demonstrated sex-specific changes in cardiovascular and hepatic function in rat offspring from mothers consuming a high-LA diet, with some effects associated with reduced LA concentration in the postnatal diet. At this time, the impact of a high-maternal-LA diet on offspring brain development and the potential for the postnatal diet to alter any adverse changes are unknown. Rat offspring from mothers fed low- (LLA) or high-LA (HLA) diets during pregnancy and lactation were weaned at postnatal day 25 (PN25) and fed LLA or HLA diets until sacrifice in adulthood (PN180). In the offspring's brains, the postnatal HLA diet increased docosapentaenoate in males. The maternal HLA diet increased LA, arachidonate, docosapentaenoate, C18:0 dimethylacetal (DMA), C16:0 DMA, C16:0 DMA/C16:0, and C18:0 DMA/C18:0, but decreased eoicosenoate, nervoniate, lignocerate, and oleate in males. Maternal and postnatal HLA diets reduced oleate and vaccenate and had an interaction effect on myristate, palmitoleate, and eicosapentaenoate in males. In females, maternal HLA diet increased eicosadienoate. Postnatal HLA diet increased stearate and docosapentaenoate. Maternal and postnatal HLA diets had an interaction effect on oleate, arachidate, and docosahexaenoic acid (DHA)/omega (n)-6 docosapentaenoic acid (DPA) in females. Postnatal HLA diet decreased DHA/n-6 DPA in males and females. Postnatal HLA diet increased plasma endocannabinoids (arachidonoyl ethanolamide and 2-arachidonoyl glycerol), as well as other N-acyl ethanolamides and testosterone. HLA diet alters brain fatty acids, plasma endocannabinoids, and plasmalogen concentrations in a development-specific and sex-specific manner.
Subject(s)
Brain , Endocannabinoids , Fatty Acids , Linoleic Acid , Plasmalogens , Female , Animals , Male , Pregnancy , Rats , Brain/metabolism , Fatty Acids/blood , Fatty Acids/metabolism , Endocannabinoids/blood , Endocannabinoids/metabolism , Linoleic Acid/blood , Plasmalogens/blood , Plasmalogens/metabolism , Prenatal Exposure Delayed Effects/blood , Sex Characteristics , Sex FactorsABSTRACT
Introduction: The endocannabinoid system (ECS), named after the chemical compounds found in the cannabis plant, is a regulatory network of neurotransmitters, receptors, and enzymes that plays crucial roles in skin health and disease. Endogenous ligands of the ECS, called endocannabinoids, have proven to be important regulators of immune responses. One of the most prevalent endocannabinoids, arachidonoylethanolamide (also known as anandamide), is known for its anti-inflammatory effects. Langerhans cells (LCs) are the sole antigen-presenting cells present in the human epidermis. They serve as the first line of defense against pathogens and are essential for the skin's specific immune responses and play a critical role in maintaining tissue homeostasis; however, little is known about the effect of endocannabinoids on these cells. Our research aimed to provide the connection between monocyte-derived Langerhans cells (moLCs) and the ECS, shedding light on their collaborative roles in immune homeostasis and inflammation. Methods: Human monocytes were differentiated into moLCs using established protocols. Anandamide was applied during the differentiation process to test its effect on the viability, marker expression, and cytokine production of the cells, as well as in short term treatments for intracellular calcium measurement. TLR ligands applied after the differentiation protocol were used to activate moLCs. The impact of anandamide on the functionality of moLCs was further assessed using differential gene expression analysis of bulk RNA-Seq data, moLC-T cell cocultures, while ELISpot was employed to determine polarization of T cells activated in the aforementioned cocultures. Results: Anandamide did not significantly affect the viability of moLCs up to 10 µM. When applied during the differentiation process it had only a negligible effect on CD207 expression, the prototypic marker of LCs; however, there was an observed reduction in CD1a expression by moLCs. Anandamide had no significant effects on the maturation status of moLCs, nor did it affect the maturation induced by TLR3 and TLR7/8 agonists. MoLCs differentiated in the presence of anandamide did however show decreased production of CXCL8, IL-6, IL-10 and IL-12 cytokines induced by TLR3 and TLR7/8 activation. Anandamide-treated moLCs showed an increased capability to activate naïve T cells; however, not to the level seen with combined TLR agonism. RNA sequencing analysis of moLCs differentiated with anandamide showed modest changes compared to control cells but did reveal an inhibitory effect on oxidative phosphorylation specifically in activated moLCs. Anandamide also promoted the polarization of naïve T cells towards a Th1 phenotype. Discussion: Our results show that anandamide has nuanced effects on the differentiation, maturation, cytokine secretion, metabolism and function of activated moLCs. Among these changes the decrease in CD1a expression on moLCs holds promise to selectively dampen inflammation induced by CD1a restricted T cells, which have been implicated as drivers of inflammation in common inflammatory skin conditions such as psoriasis, atopic dermatitis and contact dermatitis.
Subject(s)
Arachidonic Acids , Endocannabinoids , Homeostasis , Langerhans Cells , Monocytes , Polyunsaturated Alkamides , Endocannabinoids/pharmacology , Endocannabinoids/metabolism , Humans , Polyunsaturated Alkamides/pharmacology , Langerhans Cells/immunology , Langerhans Cells/metabolism , Langerhans Cells/drug effects , Arachidonic Acids/pharmacology , Monocytes/immunology , Monocytes/metabolism , Monocytes/drug effects , Cytokines/metabolism , Cell Differentiation/drug effects , Cell Differentiation/immunology , Cells, Cultured , Skin/immunology , Skin/metabolism , Inflammation/immunology , Inflammation/metabolismABSTRACT
With impaired retinal ganglion cell (RGC) function and eventual RGC death, there is a heightened risk of experiencing glaucoma-induced blindness or other optic neuropathies. Poor RGC efficiency leads to limited transmission of visual signals between the retina and the brain by RGC axons. Increased focus on studying lipid messengers found in neurons such as endocannabinoids (eCBs) has importance due to their potential axonal pathway regenerative properties. 2-Arachidonoylglycerol (2-AG), a common eCB, is synthesized from an sn-1 hydrolysis reaction between diacylglycerol (DAG) and diacylglycerol lipase (DAGL). Examination of DAG production allows for future downstream analysis in relation to DAGL functionality. Here, we describe protocol guidelines for extracting RGCs from mouse retinas and subsequent mass spectrometry analysis of the DAG content present within the RGCs.
Subject(s)
Diglycerides , Retinal Ganglion Cells , Signal Transduction , Retinal Ganglion Cells/metabolism , Animals , Mice , Diglycerides/metabolism , Endocannabinoids/metabolism , Glycerides/metabolism , Lipoprotein Lipase/metabolism , Arachidonic Acids/metabolism , Mass Spectrometry/methods , Retina/metabolismABSTRACT
Circadian rhythms are biological rhythms that originate from the "master circadian clock," called the suprachiasmatic nucleus (SCN). SCN orchestrates the circadian rhythms using light as a chief zeitgeber, enabling humans to synchronize their daily physio-behavioral activities with the Earth's light-dark cycle. However, chronic/ irregular photic disturbances from the retina via the retinohypothalamic tract (RHT) can disrupt the amplitude and the expression of clock genes, such as the period circadian clock 2, causing circadian rhythm disruption (CRd) and associated neuropathologies. The present review discusses neuromodulation across the RHT originating from retinal photic inputs and modulation offered by endocannabinoids as a function of mitigation of the CRd and associated neuro-dysfunction. Literature indicates that cannabinoid agonists alleviate the SCN's ability to get entrained to light by modulating the activity of its chief neurotransmitter, i.e., γ-aminobutyric acid, thus preventing light-induced disruption of activity rhythms in laboratory animals. In the retina, endocannabinoid signaling modulates the overall gain of the retinal ganglion cells by regulating the membrane currents (Ca2+, K+, and Cl- channels) and glutamatergic neurotransmission of photoreceptors and bipolar cells. Additionally, endocannabinoids signalling also regulate the high-voltage-activated Ca2+ channels to mitigate the retinal ganglion cells and intrinsically photosensitive retinal ganglion cells-mediated glutamate release in the SCN, thus regulating the RHT-mediated light stimulation of SCN neurons to prevent excitotoxicity. As per the literature, cannabinoid receptors 1 and 2 are becoming newer targets in drug discovery paradigms, and the involvement of endocannabinoids in light-induced CRd through the RHT may possibly mitigate severe neuropathologies.
Subject(s)
Circadian Rhythm , Endocannabinoids , Retina , Endocannabinoids/metabolism , Endocannabinoids/physiology , Humans , Animals , Circadian Rhythm/physiology , Retina/physiology , Retina/metabolism , Suprachiasmatic Nucleus/physiology , Suprachiasmatic Nucleus/drug effectsABSTRACT
The reticular thalamic nucleus (RTN) is a thin shell that covers the dorsal thalamus and controls the overall information flow from the thalamus to the cerebral cortex through GABAergic projections that contact thalamo-cortical neurons (TC). RTN neurons receive glutamatergic afferents fibers from neurons of the sixth layer of the cerebral cortex and from TC collaterals. The firing mode of RTN neurons facilitates the generation of sleep-wake cycles; a tonic mode or desynchronized mode occurs during wake and REM sleep and a burst-firing mode or synchronized mode is associated with deep sleep. Despite the presence of cannabinoid receptors CB1 (CB1Rs) and mRNA that encodes these receptors in RTN neurons, there are few works that have analyzed the participation of endocannabinoid-mediated transmission on the electrical activity of RTN. Here, we locally blocked or activated CB1Rs in ketamine anesthetized rats to analyze the spontaneous extracellular spiking activity of RTN neurons. Our results show the presence of a tonic endocannabinoid input, since local infusion of AM 251, an antagonist/inverse agonist, modifies RTN neurons electrical activity; furthermore, local activation of CB1Rs by anandamide or WIN 55212-2 produces heterogeneous effects in the basal spontaneous spiking activity, where the main effect is an increase in the spiking rate accompanied by a decrease in bursting activity in a dose-dependent manner; this effect is inhibited by AM 251. In addition, previous activation of GABA-A receptors suppresses the effects of CB1Rs on reticular neurons. Our results show that local activation of CB1Rs primarily diminishes the burst firing mode of RTn neurons.
Subject(s)
Arachidonic Acids , Ketamine , Morpholines , Neurons , Receptor, Cannabinoid, CB1 , Animals , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Male , Rats , Neurons/drug effects , Neurons/physiology , Ketamine/pharmacology , Arachidonic Acids/pharmacology , Morpholines/pharmacology , Pyrazoles/pharmacology , Endocannabinoids/pharmacology , Endocannabinoids/metabolism , Rats, Wistar , Piperidines/pharmacology , Benzoxazines/pharmacology , Action Potentials/drug effects , Action Potentials/physiology , Polyunsaturated Alkamides/pharmacology , Naphthalenes/pharmacology , Cannabinoid Receptor Agonists/pharmacology , Anesthetics, Dissociative/pharmacologyABSTRACT
Brain edema is a critical complication arising from stroke and traumatic brain injury (TBI) with an important impact on patient recovery and can lead to long-term consequences. Therapeutic options to reduce edema progression are limited with variable patient outcomes. Aquaporin 4 (AQP4) is a water channel that allows bidirectional water diffusion across the astrocyte membrane and participates in the distinct phases of cerebral edema. The absence or inhibition of this channel has been demonstrated to ameliorate edema and brain damage. The endocannabinoid system (ECS) is a neuromodulator system with a wide expression in the brain and its activation has shown neuroprotective properties in diverse models of neuronal damage. This review describes and discusses the major features of ECS and AQP4 and their role during brain damage, observing that ECS stimulation reduces edema and injury size in diverse models of brain damage, however, the relationship between AQP4 expression and dynamics and ECS activation remains unclear. The research on these topics holds promising therapeutic implications for the treatment of brain edema following stroke and TBI.
Subject(s)
Aquaporin 4 , Brain Edema , Brain Injuries , Endocannabinoids , Endocannabinoids/metabolism , Aquaporin 4/metabolism , Humans , Animals , Brain Edema/metabolism , Brain Edema/etiology , Brain Injuries/metabolism , Brain Injuries, Traumatic/metabolismABSTRACT
Neurolipids comprise a diverse class of bioactive lipids that include molecules capable of activating G proteincoupled receptors, thereby inducing systemic effects that contribute to the maintenance of homeostasis. Dementia, a nonspecific brain disorder characterized by a common set of signs and symptoms, usually arises subsequent to brain injuries or diseases and is often associated with the aging process. Individuals affected by dementia suffer from the disruption of several neurotransmitter and neuromodulatory systems, among which neurolipids play an important role, including the endocannabinoid, lysophosphatidic acid and sphingosine 1phosphate systems. In this review, we present an overview of the most recent and pertinent findings regarding the involvement of these neurolipidic systems in dementia, including data from a wide range of both in vitro and in vivo experiments as well as clinical trials.
Subject(s)
Dementia , Lysophospholipids , Humans , Dementia/drug therapy , Dementia/metabolism , Lysophospholipids/metabolism , Animals , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Endocannabinoids/metabolism , Receptors, G-Protein-Coupled/metabolism , Brain/metabolism , Brain/drug effects , Neurotransmitter Agents/metabolismABSTRACT
BACKGROUND: Posttraumatic headache (PTH) is a common and debilitating symptom following repetitive mild traumatic brain injury (rmTBI), and it mainly resembles a migraine-like phenotype. While modulation of the endocannabinoid system (ECS) is effective in treating TBI and various types of pain including migraine, the role of augmentation of endocannabinoids in treating PTH has not been investigated. METHODS: Repetitive mild TBI was induced in male C57BL/6J mice using the non-invasive close-head impact model of engineered rotational acceleration (CHIMERA). Periorbital allodynia was assessed using von Frey filaments and determined by the "Up-Down" method. Immunofluorescence staining was employed to investigate glial cell activation and calcitonin gene-related peptide (CGRP) expression in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) of the rmTBI mice. Levels of 2-arachidonoyl glycerol (2-AG), anandamide (AEA), and arachidonic acid (AA) in the TG, medulla (including TNC), and periaqueductal gray (PAG) were measured by mass spectrometry. The therapeutic effect of endocannabinoid modulation on PTH was also assessed. RESULTS: The rmTBI mice exhibited significantly increased cephalic pain hypersensitivity compared to the sham controls. MJN110, a potent and selective inhibitor of the 2-AG hydrolytic enzyme monoacylglycerol lipase (MAGL), dose-dependently attenuated periorbital allodynia in the rmTBI animals. Administration of CGRP at 0.01 mg/kg reinstated periorbital allodynia in the rmTBI animals on days 33 and 45 post-injury but had no effect in the sham and MJN110 treatment groups. Activation of glial cells along with increased production of CGRP in the TG and TNC at 7 and 14 days post-rmTBI were attenuated by MJN110 treatment. The anti-inflammatory and anti-nociceptive effects of MJN110 were partially mediated by cannabinoid receptor activation, and the pain-suppressive effect of MJN110 was completely blocked by co-administration of DO34, an inhibitor of 2-AG synthase. The levels of 2-AG in TG, TNC and PAG were decreased in TBI animals, significantly elevated and further reduced by the selective inhibitors of 2-AG hydrolytic and synthetic enzymes, respectively. CONCLUSION: Enhancing endogenous levels of 2-AG appears to be an effective strategy for the treatment of PTH by attenuating pain initiation and transmission in the trigeminal pathway and facilitating descending pain inhibitory modulation.
Subject(s)
Arachidonic Acids , Brain Concussion , Endocannabinoids , Glycerides , Mice, Inbred C57BL , Post-Traumatic Headache , Animals , Endocannabinoids/metabolism , Male , Brain Concussion/complications , Brain Concussion/drug therapy , Arachidonic Acids/pharmacology , Mice , Post-Traumatic Headache/etiology , Post-Traumatic Headache/drug therapy , Glycerides/metabolism , Disease Models, Animal , Hyperalgesia/drug therapy , Hyperalgesia/etiology , Hydrolysis , Calcitonin Gene-Related Peptide/metabolism , Trigeminal Ganglion/metabolism , Trigeminal Ganglion/drug effects , Piperidines/pharmacology , Piperidines/therapeutic use , Polyunsaturated Alkamides/pharmacologyABSTRACT
BACKGROUND: Major depressive disorder (MDD) is a highly prevalent mental health disorder with females experiencing higher rates of depression (11.6%), anxiety (15.7%) and physiological distress (14.5%) than males. Recently, the Endocannabinoid system (ECS) has been proposed to be a key contributing factor in the pathogenesis and symptom severity of MDD due to its role in neurotransmitter production, inflammatory response and even regulation of the female reproductive cycle. This review critically evaluates evidence regarding ECS levels in female-sexed individuals with depressive disorders to further understand ECS role. MATERIALS AND METHODS: A systematic literature review of available research published prior to April 2022 was identified using PubMed (U.S. National Library of Medicine), CINAHL (EBSCO), Web of Science, AMED and Scopus (Elsevier). Studies were included if they reported ECS analysis of female-sexed individuals with depression and were excluded if they did not differentiate results between sexes, assessed mental health conditions other than depression, tested efficacy of endocannabinoid/n-acylethanolamine/cannabis or marijuana administration and that were unable to be translated. Critical appraisal of each included study was undertaken using the Joanna Briggs Institute Critical Appraisal Tool for Systematic Reviews. RESULTS: The 894 located citations were screened for duplicates (n = 357) and eligibility by title and abstract (n = 501). The full text of 33 studies were reviewed, and 7 studies were determined eligible for inclusion. These studies indicated that depressed female-sexed individuals have altered levels of ECS however no significant pattern was identified due to variability of study outcomes and measures, limiting overall interpretation. DISCUSSION: This review suggests potential involvement of ECS in underlying mechanisms of MDD in female sexed-individuals, however no pattern was able to be determined. A major contributor to the inability to attain reliable and valid understanding of the ECS levels in female-sexed individuals with depression was the inconsistency of depression screening tools, inclusion criteria's and analysis methods used to measure eCBs. Future studies need to implement more standardised methodology to gain a deeper understanding of ECS in female-sexed individuals with depressive disorders. TRIAL REGISTRATION : This review was submitted to PROSPERO for approval in April 2022 (Registration #CRD42022324212).
Subject(s)
Depressive Disorder, Major , Endocannabinoids , Humans , Endocannabinoids/metabolism , Female , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/psychology , Sex Factors , MaleABSTRACT
Emerging research links the endocannabinoid system to gut microbiota, influencing nociception, mood, and immunity, yet the molecular interactions remain unclear. This study focused on the effects of probiotics on ECS markers-cannabinoid receptor type 2 (CB2) and fatty acid amide hydrolase (FAAH)-in dancers, a group selected due to their high exposure to physical and psychological stress. In a double-blind, placebo-controlled trial (ClinicalTrials.gov NCT05567653), 15 dancers were assigned to receive either a 12-week regimen of Lactobacillus helveticus Rosell-52 and Bifidobacterium longum Rosell-17 or a placebo (PLA: n = 10, PRO: n = 5). There were no significant changes in CB2 (probiotic: 0.55 to 0.29 ng/mL; placebo: 0.86 to 0.72 ng/mL) or FAAH levels (probiotic: 5.93 to 6.02 ng/mL; placebo: 6.46 to 6.94 ng/mL; p > 0.05). A trend toward improved sleep quality was observed in the probiotic group, while the placebo group showed a decline (PRO: from 1.4 to 1.0; PLA: from 0.8 to 1.2; p = 0.07841). No other differences were noted in assessed outcomes (pain and fatigue). Probiotic supplementation showed no significant impact on CB2 or FAAH levels, pain, or fatigue but suggested potential benefits for sleep quality, suggesting an area for further research.