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Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening.
Marcus DJ, Bedse G, Gaulden AD, Ryan JD, Kondev V, Winters ND, Rosas-Vidal LE, Altemus M, Mackie K, Lee FS, Delpire E, Patel S
(2020) Neuron 105: 1062-1076.e6
MeSH Terms: Animals, Anxiety, Arachidonic Acids, Basolateral Nuclear Complex, Endocannabinoids, Glutamic Acid, Glycerides, Male, Mice, Neural Pathways, Prefrontal Cortex, Restraint, Physical, Stress, Psychological, Synaptic Transmission
Show Abstract · Added March 3, 2020
Functional coupling between the amygdala and the dorsomedial prefrontal cortex (dmPFC) has been implicated in the generation of negative affective states; however, the mechanisms by which stress increases amygdala-dmPFC synaptic strength and generates anxiety-like behaviors are not well understood. Here, we show that the mouse basolateral amygdala (BLA)-prelimbic prefrontal cortex (plPFC) circuit is engaged by stress and activation of this pathway in anxiogenic. Furthermore, we demonstrate that acute stress exposure leads to a lasting increase in synaptic strength within a reciprocal BLA-plPFC-BLA subcircuit. Importantly, we identify 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid signaling as a key mechanism limiting glutamate release at BLA-plPFC synapses and the functional collapse of multimodal 2-AG signaling as a molecular mechanism leading to persistent circuit-specific synaptic strengthening and anxiety-like behaviors after stress exposure. These data suggest that circuit-specific impairment in 2-AG signaling could facilitate functional coupling between the BLA and plPFC and the translation of environmental stress to affective pathology.
Copyright © 2019 Elsevier Inc. All rights reserved.
0 Communities
2 Members
0 Resources
14 MeSH Terms
Arachidonic Acid Kills Staphylococcus aureus through a Lipid Peroxidation Mechanism.
Beavers WN, Monteith AJ, Amarnath V, Mernaugh RL, Roberts LJ, Chazin WJ, Davies SS, Skaar EP
(2019) mBio 10:
MeSH Terms: Animals, Anti-Bacterial Agents, Arachidonic Acid, Brain, Dose-Response Relationship, Drug, Drug Resistance, Bacterial, Female, Kidney, Lipid Peroxidation, Lipids, Mice, Mice, Inbred BALB C, Microbial Sensitivity Tests, Mutation, Neutrophils, Oxidative Stress, Reactive Oxygen Species, Spleen, Staphylococcal Infections, Staphylococcus aureus, Teichoic Acids
Show Abstract · Added March 11, 2020
infects every niche of the human host. In response to microbial infection, vertebrates have an arsenal of antimicrobial compounds that inhibit bacterial growth or kill bacterial cells. One class of antimicrobial compounds consists of polyunsaturated fatty acids, which are highly abundant in eukaryotes and encountered by at the host-pathogen interface. Arachidonic acid (AA) is one of the most abundant polyunsaturated fatty acids in vertebrates and is released in large amounts during the oxidative burst. Most of the released AA is converted to bioactive signaling molecules, but, independently of its role in inflammatory signaling, AA is toxic to Here, we report that AA kills through a lipid peroxidation mechanism whereby AA is oxidized to reactive electrophiles that modify macromolecules, eliciting toxicity. This process is rescued by cotreatment with antioxidants as well as in a strain genetically inactivated for (USA300 mutant) that produces lower levels of reactive oxygen species. However, resistance to AA stress in the USA300 mutant comes at a cost, making the mutant more susceptible to β-lactam antibiotics and attenuated for pathogenesis in a murine infection model compared to the parental methicillin-resistant (MRSA) strain, indicating that resistance to AA toxicity increases susceptibility to other stressors encountered during infection. This report defines the mechanism by which AA is toxic to and identifies lipid peroxidation as a pathway that can be modulated for the development of future therapeutics to treat infections. Despite the ability of the human immune system to generate a plethora of molecules to control infections, is among the pathogens with the greatest impact on human health. One class of host molecules toxic to consists of polyunsaturated fatty acids. Here, we investigated the antibacterial properties of arachidonic acid, one of the most abundant polyunsaturated fatty acids in humans, and discovered that the mechanism of toxicity against proceeds through lipid peroxidation. A better understanding of the molecular mechanisms by which the immune system kills , and by which avoids host killing, will enable the optimal design of therapeutics that complement the ability of the vertebrate immune response to eliminate infections.
Copyright © 2019 Beavers et al.
0 Communities
1 Members
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21 MeSH Terms
Aspects of Prostaglandin Glycerol Ester Biology.
Kingsley PJ, Rouzer CA, Morgan AJ, Patel S, Marnett LJ
(2019) Adv Exp Med Biol 1161: 77-88
MeSH Terms: Animals, Arachidonic Acids, Cyclooxygenase 2, Endocannabinoids, Glycerides, Glyceryl Ethers, Prostaglandins
Show Abstract · Added March 12, 2020
The Cyclooxygenase enzymes (COX-1 and COX-2) incorporate 2 molecules of O into arachidonic acid (AA), resulting in an array of bioactive prostaglandins. However, much work has been done showing that COX-2 will perform this reaction on several different AA-containing molecules, most importantly, the endocannabinoid 2-arachidonoylglycerol (2-AG). The products of 2-AG oxygenation, prostaglandin glycerol esters (PG-Gs), are analogous to canonical prostaglandins. This chapter reviews the literature detailing the production, metabolism, and bioactivity of these compounds, as well as their detection in intact animals.
0 Communities
1 Members
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MeSH Terms
Isolevuglandins and cardiovascular disease.
Davies SS, May-Zhang LS
(2018) Prostaglandins Other Lipid Mediat 139: 29-35
MeSH Terms: Arachidonic Acid, Atherosclerosis, Cardiovascular Diseases, Humans, Lipid Peroxidation, Lipids
Show Abstract · Added October 26, 2018
Isolevuglandins are 4-ketoaldehydes formed by peroxidation of arachidonic acid. Isolevuglandins react rapidly with primary amines including the lysyl residues of proteins to form irreversible covalent modifications. This review highlights evidence for the potential role of isolevuglandin modification in the disease processes, especially atherosclerosis, and some of the tools including small molecule dicarbonyl scavengers utilized to assess their contributions to disease.
Copyright © 2018. Published by Elsevier Inc.
1 Communities
2 Members
0 Resources
6 MeSH Terms
The Cytochrome P450 Slow Metabolizers CYP2C9*2 and CYP2C9*3 Directly Regulate Tumorigenesis via Reduced Epoxyeicosatrienoic Acid Production.
Sausville LN, Gangadhariah MH, Chiusa M, Mei S, Wei S, Zent R, Luther JM, Shuey MM, Capdevila JH, Falck JR, Guengerich FP, Williams SM, Pozzi A
(2018) Cancer Res 78: 4865-4877
MeSH Terms: Animals, Arachidonic Acid, Arachidonic Acids, Carcinogenesis, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cytochrome P-450 CYP2C9, Cytochrome P-450 Enzyme System, Eicosanoids, Endothelial Cells, Humans, Mice, Polymorphism, Single Nucleotide, Xenograft Model Antitumor Assays
Show Abstract · Added October 25, 2018
Increased expression of cytochrome P450 CYP2C9, together with elevated levels of its products epoxyeicosatrienoic acids (EET), is associated with aggressiveness in cancer. Cytochrome P450 variants and encode proteins with reduced enzymatic activity, and individuals carrying these variants metabolize drugs more slowly than individuals with wild-type , potentially affecting their response to drugs and altering their risk of disease. Although genetic differences in CYP2C9-dependent oxidation of arachidonic acid (AA) have been reported, the roles of CYP2C9*2 and CYP2C9*3 in EET biosynthesis and their relevance to disease are unknown. Here, we report that CYP2C9*2 and CYP2C9*3 metabolize AA less efficiently than CYP2C9*1 and that they play a role in the progression of non-small cell lung cancer (NSCLC) via impaired EET biosynthesis. When injected into mice, NSCLC cells expressing CYP2C9*2 and CYP2C9*3 produced lower levels of EETs and developed fewer, smaller, and less vascularized tumors than cells expressing CYP2C9*1. Moreover, endothelial cells expressing these two variants proliferated and migrated less than cells expressing CYP2C*1. Purified CYP2C9*2 and CYP2C9*3 exhibited attenuated catalytic efficiency in producing EETs, primarily due to impaired reduction of these two variants by NADPH-P450 reductase. Loss-of-function SNPs within and were associated with improved survival in female cases of NSCLC. Thus, decreased EET biosynthesis represents a novel mechanism whereby CYPC29*2 and CYP2C9*3 exert a direct protective role in NSCLC development. These findings report single nucleotide polymorphisms in the human CYP2C9 genes, and , exert a direct protective role in tumorigenesis by impairing EET biosynthesis. .
©2018 American Association for Cancer Research.
0 Communities
2 Members
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14 MeSH Terms
Detection of Cyclooxygenase-2-Derived Oxygenation Products of the Endogenous Cannabinoid 2-Arachidonoylglycerol in Mouse Brain.
Morgan AJ, Kingsley PJ, Mitchener MM, Altemus M, Patrick TA, Gaulden AD, Marnett LJ, Patel S
(2018) ACS Chem Neurosci 9: 1552-1559
MeSH Terms: Animals, Arachidonic Acids, Brain, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Endocannabinoids, Esters, Female, Glycerides, Inflammation, Lipopolysaccharides, Male, Mice, Inbred C57BL, Mice, Transgenic, Monoacylglycerol Lipases, Neurons, Oxidation-Reduction, Prostaglandins
Show Abstract · Added October 8, 2018
Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandins, which are involved in immune regulation, vascular function, and synaptic signaling. COX-2 also inactivates the endogenous cannabinoid (eCB) 2-arachidonoylglycerol (2-AG) via oxygenation of its arachidonic acid backbone to form a variety of prostaglandin glyceryl esters (PG-Gs). Although this oxygenation reaction is readily observed in vitro and in intact cells, detection of COX-2-derived 2-AG oxygenation products has not been previously reported in neuronal tissue. Here we show that 2-AG is metabolized in the brain of transgenic COX-2-overexpressing mice and mice treated with lipopolysaccharide to form multiple species of PG-Gs that are detectable only when monoacylglycerol lipase is concomitantly blocked. Formation of these PG-Gs is prevented by acute pharmacological inhibition of COX-2. These data provide evidence that neuronal COX-2 is capable of oxygenating 2-AG to form a variety PG-Gs in vivo and support further investigation of the physiological functions of PG-Gs.
0 Communities
2 Members
0 Resources
18 MeSH Terms
Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior.
Shonesy BC, Parrish WP, Haddad HK, Stephenson JR, Báldi R, Bluett RJ, Marks CR, Centanni SW, Folkes OM, Spiess K, Augustin SM, Mackie K, Lovinger DM, Winder DG, Patel S, Colbran RJ
(2018) Biol Psychiatry 84: 304-315
MeSH Terms: Animals, Arachidonic Acids, Autism Spectrum Disorder, Corpus Striatum, Endocannabinoids, Glycerides, Mice, Mice, Knockout, Receptor, Adenosine A2A, Receptors, Dopamine D1, Signal Transduction, Social Behavior, Synaptic Transmission
Show Abstract · Added March 21, 2018
BACKGROUND - Endocannabinoid signaling plays an important role in regulating synaptic transmission in the striatum, a brain region implicated as a central node of dysfunction in autism spectrum disorder. Deficits in signaling mediated by the endocannabinoid 2-arachidonoylglycerol (2-AG) have been reported in mouse models of autism spectrum disorder, but a causal role for striatal 2-AG deficiency in phenotypes relevant to autism spectrum disorder has not been explored.
METHODS - Using conditional knockout mice, we examined the electrophysiological, biochemical, and behavioral effects of 2-AG deficiency by deleting its primary synthetic enzyme, diacylglycerol lipase α (DGLα), from dopamine D receptor-expressing or adenosine A2a receptor-expressing medium spiny neurons (MSNs) to determine the role of 2-AG signaling in striatal direct or indirect pathways, respectively. We then used viral-mediated deletion of DGLα to study the effects of 2-AG deficiency in the ventral and dorsal striatum.
RESULTS - Targeted deletion of DGLα from direct-pathway MSNs caused deficits in social interaction, excessive grooming, and decreased exploration of a novel environment. In contrast, deletion from indirect-pathway MSNs had no effect on any measure of behavior examined. Loss of 2-AG in direct-pathway MSNs also led to increased glutamatergic drive, which is consistent with a loss of retrograde feedback inhibition. Subregional DGLα deletion from the dorsal striatum produced deficits in social interaction, whereas deletion from the ventral striatum resulted in repetitive grooming.
CONCLUSIONS - These data suggest a role for 2-AG deficiency in social deficits and repetitive behavior, and they demonstrate a key role for 2-AG in regulating striatal direct-pathway MSNs.
Copyright © 2018 Society of Biological Psychiatry. All rights reserved.
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2 Members
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13 MeSH Terms
PUFA levels in erythrocyte membrane phospholipids are differentially associated with colorectal adenoma risk.
Rifkin SB, Shrubsole MJ, Cai Q, Smalley WE, Ness RM, Swift LL, Zheng W, Murff HJ
(2017) Br J Nutr 117: 1615-1622
MeSH Terms: Adenoma, Arachidonic Acid, Biomarkers, Case-Control Studies, Colorectal Neoplasms, Diet, Eicosapentaenoic Acid, Erythrocyte Membrane, Female, Humans, Logistic Models, Male, Middle Aged, Odds Ratio, Phospholipids, Risk Factors, Tennessee
Show Abstract · Added April 3, 2018
Dietary intake of PUFA has been associated with colorectal neoplasm risk; however, results from observational studies have been inconsistent. Most prior studies have utilised self-reported dietary measures to assess fatty acid exposure which might be more susceptible to measurement error and biases compared with biomarkers. The purpose of this study was to determine whether erythrocyte phospholipid membrane PUFA percentages are associated with colorectal adenoma risk. We included data from 904 adenoma cases and 835 polyp-free controls who participated in the Tennessee Colorectal Polyp Study, a large colonoscopy-based case-control study. Erythrocyte membrane PUFA percentages were measured using GC. Conditional logistic regression was used to calculate adjusted OR for risk of colorectal adenomas with erythrocyte membrane PUFA. Higher erythrocyte membrane percentages of arachidonic acid was associated with an increased risk of colorectal adenomas (adjusted OR 1·66; 95 % CI 1·05, 2·62, P trend=0·02) comparing the highest tertile to the lowest tertile. The effect size for arachidonic acid was more pronounced when restricting the analysis to advanced adenomas only. Higher erythrocyte membrane EPA percentages were associated with a trend towards a reduced risk of advanced colorectal adenomas (P trend=0·05). Erythrocyte membrane arachidonic acid percentages are associated with an increased risk of colorectal adenomas.
0 Communities
1 Members
0 Resources
MeSH Terms
Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety.
Bedse G, Hartley ND, Neale E, Gaulden AD, Patrick TA, Kingsley PJ, Uddin MJ, Plath N, Marnett LJ, Patel S
(2017) Biol Psychiatry 82: 488-499
MeSH Terms: Adaptation, Ocular, Animals, Anti-Anxiety Agents, Anxiety, Arachidonic Acids, Benzodioxoles, Brain, Cannabinoid Receptor Agonists, Cyclohexanols, Disease Models, Animal, Dronabinol, Endocannabinoids, Excitatory Postsynaptic Potentials, Glycerides, Heterocyclic Compounds, 1-Ring, Locomotion, Male, Mice, Mice, Inbred ICR, Piperidines, Pyridines, Signal Transduction
Show Abstract · Added April 26, 2017
BACKGROUND - Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (N-arachidonylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood.
METHODS - We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice.
RESULTS - Selective 2-AG augmentation reduced anxiety in the light/dark box assay and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct cannabinoid receptor 1 stimulation with Δ-tetrahydrocannabinol. Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation.
CONCLUSIONS - Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than was previously appreciated.
Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
0 Communities
3 Members
0 Resources
22 MeSH Terms
Endocannabinoid signalling modulates susceptibility to traumatic stress exposure.
Bluett RJ, Báldi R, Haymer A, Gaulden AD, Hartley ND, Parrish WP, Baechle J, Marcus DJ, Mardam-Bey R, Shonesy BC, Uddin MJ, Marnett LJ, Mackie K, Colbran RJ, Winder DG, Patel S
(2017) Nat Commun 8: 14782
MeSH Terms: Amygdala, Animals, Anxiety, Arachidonic Acids, Behavior, Animal, Benzodioxoles, Disease Susceptibility, Dronabinol, Endocannabinoids, Excitatory Postsynaptic Potentials, Female, Glutamates, Glycerides, Hippocampus, Lipoprotein Lipase, Male, Mice, Inbred ICR, Mice, Knockout, Phenotype, Piperidines, Resilience, Psychological, Signal Transduction, Stress, Psychological, Synapses
Show Abstract · Added April 7, 2017
Stress is a ubiquitous risk factor for the exacerbation and development of affective disorders including major depression and posttraumatic stress disorder. Understanding the neurobiological mechanisms conferring resilience to the adverse consequences of stress could have broad implications for the treatment and prevention of mood and anxiety disorders. We utilize laboratory mice and their innate inter-individual differences in stress-susceptibility to demonstrate a critical role for the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) in stress-resilience. Specifically, systemic 2-AG augmentation is associated with a stress-resilient phenotype and enhances resilience in previously susceptible mice, while systemic 2-AG depletion or CB1 receptor blockade increases susceptibility in previously resilient mice. Moreover, stress-resilience is associated with increased phasic 2-AG-mediated synaptic suppression at ventral hippocampal-amygdala glutamatergic synapses and amygdala-specific 2-AG depletion impairs successful adaptation to repeated stress. These data indicate amygdala 2-AG signalling mechanisms promote resilience to adverse effects of acute traumatic stress and facilitate adaptation to repeated stress exposure.
0 Communities
4 Members
0 Resources
24 MeSH Terms