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Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors.
Bedse G, Bluett RJ, Patrick TA, Romness NK, Gaulden AD, Kingsley PJ, Plath N, Marnett LJ, Patel S
(2018) Transl Psychiatry 8: 92
MeSH Terms: Amidohydrolases, Animals, Anti-Anxiety Agents, Anxiety Disorders, Behavior, Animal, Benzodioxoles, Body Temperature, Brain, Carbamates, Endocannabinoids, Female, Locomotion, Male, Maze Learning, Mice, Inbred C57BL, Mice, Inbred ICR, Monoacylglycerol Lipases, Piperazines, Piperidines, Pyridines, Stress, Psychological
Show Abstract · Added April 12, 2019
Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light-dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.
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MeSH Terms
Selective killing of with pH-responsive helix-coil conformation transitionable antimicrobial polypeptides.
Xiong M, Bao Y, Xu X, Wang H, Han Z, Wang Z, Liu Y, Huang S, Song Z, Chen J, Peek RM, Yin L, Chen LF, Cheng J
(2017) Proc Natl Acad Sci U S A 114: 12675-12680
MeSH Terms: Amines, Animals, Anti-Bacterial Agents, Antimicrobial Cationic Peptides, Disease Models, Animal, Female, Glutamic Acid, Helicobacter Infections, Helicobacter pylori, Hydrogen-Ion Concentration, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Organ Specificity, Protein Conformation, alpha-Helical, Static Electricity, Stomach
Show Abstract · Added March 14, 2018
Current clinical treatment of infection, the main etiological factor in the development of gastritis, gastric ulcers, and gastric carcinoma, requires a combination of at least two antibiotics and one proton pump inhibitor. However, such triple therapy suffers from progressively decreased therapeutic efficacy due to the drug resistance and undesired killing of the commensal bacteria due to poor selectivity. Here, we report the development of antimicrobial polypeptide-based monotherapy, which can specifically kill under acidic pH in the stomach while inducing minimal toxicity to commensal bacteria under physiological pH. Specifically, we designed a class of pH-sensitive, helix-coil conformation transitionable antimicrobial polypeptides (HCT-AMPs) (PGA)--(PHLG-MHH), bearing randomly distributed negatively charged glutamic acid and positively charged poly(γ-6--(methyldihexylammonium)hexyl-l-glutamate) (PHLG-MHH) residues. The HCT-AMPs showed unappreciable toxicity at physiological pH when they adopted random coiled conformation. Under acidic condition in the stomach, they transformed to the helical structure and exhibited potent antibacterial activity against , including clinically isolated drug-resistant strains. After oral gavage, the HCT-AMPs afforded comparable killing efficacy to the triple-therapy approach while inducing minimal toxicity against normal tissues and commensal bacteria, in comparison with the remarkable killing of commensal bacteria by 65% and 86% in the ileal contents and feces, respectively, following triple therapy. This strategy renders an effective approach to specifically target and kill in the stomach while not harming the commensal bacteria/normal tissues.
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17 MeSH Terms
Co-Activation of Metabotropic Glutamate Receptor 3 and Beta-Adrenergic Receptors Modulates Cyclic-AMP and Long-Term Potentiation, and Disrupts Memory Reconsolidation.
Walker AG, Sheffler DJ, Lewis AS, Dickerson JW, Foster DJ, Senter RK, Moehle MS, Lv X, Stansley BJ, Xiang Z, Rook JM, Emmitte KA, Lindsley CW, Conn PJ
(2017) Neuropsychopharmacology 42: 2553-2566
MeSH Terms: Animals, Cerebral Cortex, Conditioning, Psychological, Cyclic AMP, Hippocampus, Long-Term Potentiation, Male, Memory Consolidation, Mice, Inbred ICR, Mice, Knockout, Neurotransmitter Agents, Rats, Sprague-Dawley, Receptors, Adrenergic, beta, Receptors, Metabotropic Glutamate, Tissue Culture Techniques
Show Abstract · Added March 21, 2018
Activation of β-adrenergic receptors (βARs) enhances both the induction of long-term potentiation (LTP) in hippocampal CA1 pyramidal cells and hippocampal-dependent cognitive function. Interestingly, previous studies reveal that coincident activation of group II metabotropic glutamate (mGlu) receptors with βARs in the hippocampal astrocytes induces a large increase in cyclic-AMP (cAMP) accumulation and release of adenosine. Adenosine then acts on A adenosine receptors at neighboring excitatory Schaffer collateral terminals, which could counteract effects of activation of neuronal βARs on excitatory transmission. On the basis of this, we postulated that activation of the specific mGlu receptor subtype that mediates this response could inhibit βAR-mediated effects on hippocampal synaptic plasticity and cognitive function. Using novel mGlu receptor subtype-selective allosteric modulators along with knockout mice we now report that the effects of mGlu agonists on βAR-mediated increases in cAMP accumulation are exclusively mediated by mGlu. Furthermore, mGlu activation inhibits the ability of the βAR agonist isoproterenol to enhance hippocampal LTP, and this effect is absent in slices treated with either a glial toxin or an adenosine A receptor antagonist. Finally, systemic administration of the mGlu agonist LY379268 disrupted contextual fear memory in a manner similar to the effect of the βAR antagonist propranolol, and this effect was reversed by the mGlu-negative allosteric modulator VU0650786. Taken together, these data suggest that mGlu can influence astrocytic signaling and modulate βAR-mediated effects on hippocampal synaptic plasticity and cognitive function.
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15 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.
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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.
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4 Members
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24 MeSH Terms
The gastrin-releasing peptide analog bombesin preserves exocrine and endocrine pancreas morphology and function during parenteral nutrition.
Pierre JF, Neuman JC, Brill AL, Brar HK, Thompson MF, Cadena MT, Connors KM, Busch RA, Heneghan AF, Cham CM, Jones EK, Kibbe CR, Davis DB, Groblewski GE, Kudsk KA, Kimple ME
(2015) Am J Physiol Gastrointest Liver Physiol 309: G431-42
MeSH Terms: Amylases, Animals, Bombesin, DNA, Food, Formulated, Gastrin-Releasing Peptide, Gene Expression Regulation, Hyperglycemia, Islets of Langerhans, Lipase, Male, Mice, Mice, Inbred ICR, Pancreas, Exocrine, Pancreatic Hormones, Parenteral Nutrition
Show Abstract · Added August 2, 2016
Stimulation of digestive organs by enteric peptides is lost during total parental nutrition (PN). Here we examine the role of the enteric peptide bombesin (BBS) in stimulation of the exocrine and endocrine pancreas during PN. BBS protects against exocrine pancreas atrophy and dysfunction caused by PN. BBS also augments circulating insulin levels, suggesting an endocrine pancreas phenotype. While no significant changes in gross endocrine pancreas morphology were observed, pancreatic islets isolated from BBS-treated PN mice showed a significantly enhanced insulin secretion response to the glucagon-like peptide-1 (GLP-1) agonist exendin-4, correlating with enhanced GLP-1 receptor expression. BBS itself had no effect on islet function, as reflected in low expression of BBS receptors in islet samples. Intestinal BBS receptor expression was enhanced in PN with BBS, and circulating active GLP-1 levels were significantly enhanced in BBS-treated PN mice. We hypothesized that BBS preserved islet function indirectly, through the enteroendocrine cell-pancreas axis. We confirmed the ability of BBS to directly stimulate intestinal enteroid cells to express the GLP-1 precursor preproglucagon. In conclusion, BBS preserves the exocrine and endocrine pancreas functions during PN; however, the endocrine stimulation is likely indirect, through the enteroendocrine cell-pancreas axis.
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16 MeSH Terms
Bombesin Preserves Goblet Cell Resistin-Like Molecule β During Parenteral Nutrition but Not Other Goblet Cell Products.
Busch RA, Heneghan AF, Pierre JF, Neuman JC, Reimer CA, Wang X, Kimple ME, Kudsk KA
(2016) JPEN J Parenter Enteral Nutr 40: 1042-9
MeSH Terms: Animals, Bombesin, Goblet Cells, Hormones, Ectopic, Ileum, Immunity, Innate, Interleukin-13, Interleukin-4, Male, Mice, Mice, Inbred ICR, Mucin-2, Paneth Cells, Parenteral Nutrition, Trefoil Factor-3
Show Abstract · Added August 2, 2016
INTRODUCTION - Parenteral nutrition (PN) increases the risk of infection in critically ill patients and is associated with defects in gastrointestinal innate immunity. Goblet cells produce mucosal defense compounds, including mucin (principally MUC2), trefoil factor 3 (TFF3), and resistin-like molecule β (RELMβ). Bombesin (BBS), a gastrin-releasing peptide analogue, experimentally reverses PN-induced defects in Paneth cell innate immunity. We hypothesized that PN reduces goblet cell product expression and PN+BBS would reverse these PN-induced defects.
METHODS - Two days after intravenous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 15), PN (n = 13), or PN+BBS (15 µg tid) (n = 12) diets for 5 days. Defined segments of ileum and luminal fluid were analyzed for MUC2, TFF3, and RELMβ by quantitative reverse transcriptase polymerase chain reaction and Western blot. Th2 cytokines interleukin (IL)-4 and IL-13 were measured by enzyme-linked immunosorbent assay.
RESULTS - Compared with chow, PN significantly reduced MUC2 in ileum (P < .01) and luminal fluid (P = .01). BBS supplementation did not improve ileal or luminal MUC2 compared with PN (P > .3). Compared with chow, PN significantly reduced TFF3 in ileum (P < .02) and luminal fluid (P < .01). BBS addition did not improve ileal or luminal TFF3 compared with PN (P > .3). Compared with chow, PN significantly reduced ileal RELMβ (P < .01). BBS supplementation significantly increased ileal RELMβ to levels similar to chow (P < .03 vs PN; P > .6 vs chow). Th2 cytokines were decreased with PN and returned to chow levels with BBS.
CONCLUSION - PN significantly impairs the goblet cell component of innate mucosal immunity. BBS only preserves goblet cell RELMβ during PN but not other goblet cell products measured.
© 2015 American Society for Parenteral and Enteral Nutrition.
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15 MeSH Terms
Effects of VU0410120, a novel GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in a mouse model of autism.
Burket JA, Benson AD, Green TL, Rook JM, Lindsley CW, Conn PJ, Deutsch SI
(2015) Prog Neuropsychopharmacol Biol Psychiatry 61: 10-7
MeSH Terms: Analysis of Variance, Animals, Benzamides, Dose-Response Relationship, Drug, Glycine Plasma Membrane Transport Proteins, Male, Maze Learning, Memory, Short-Term, Mice, Mice, Inbred BALB C, Mice, Inbred ICR, Piperidines, Social Behavior, Spatial Learning, Stereotyped Behavior
Show Abstract · Added February 18, 2016
The NMDA receptor is a highly regulated glutamate-gated cationic channel receptor that has an important role in the regulation of sociability and cognition. The genetically-inbred Balb/c mouse has altered endogenous tone of NMDA receptor-mediated neurotransmission and is a model of impaired sociability, relevant to Autism Spectrum Disorders (ASDs). Because glycine is an obligatory co-agonist that works cooperatively with glutamate to promote opening of the ion channel, one prominent strategy to promote NMDA receptor-mediated neurotransmission involves inhibition of the glycine type 1 transporter (GlyT1). The current study evaluated the dose-dependent effects of VU0410120, a selective, high-affinity competitive GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in Balb/c and Swiss Webster mice. The data show that doses of VU0410120 (i.e., 18 and 30mg/kg) that improve measures of sociability and spatial working memory in the Balb/c mouse strain elicit intense stereotypic behaviors in the Swiss Webster comparator strain (i.e., burrowing and jumping). Furthermore, the data suggest that selective GlyT1 inhibition improves sociability and spatial working memory at doses that do not worsen or elicit stereotypic behaviors in a social situation in the Balb/c strain. However, the elicitation of stereotypic behaviors in the Swiss Webster comparator strain at therapeutically relevant doses of VU0410120 suggest that genetic factors (i.e., mouse strain differences) influence sensitivity to GlyT1-elicited stereotypic behaviors, and emergence of intense stereotypic behaviors may be dose-limiting side effects of this interventional strategy.
Copyright © 2015 Elsevier Inc. All rights reserved.
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15 MeSH Terms
A method to prevent protein delocalization in imaging mass spectrometry of non-adherent tissues: application to small vertebrate lens imaging.
Anderson DM, Floyd KA, Barnes S, Clark JM, Clark JI, Mchaourab H, Schey KL
(2015) Anal Bioanal Chem 407: 2311-20
MeSH Terms: Analytic Sample Preparation Methods, Animals, Crystallins, Female, Lens, Crystalline, Male, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Molecular Imaging, Protein Transport, Rats, Rats, Wistar, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Zebrafish
Show Abstract · Added February 12, 2015
MALDI imaging requires careful sample preparation to obtain reliable, high-quality images of small molecules, peptides, lipids, and proteins across tissue sections. Poor crystal formation, delocalization of analytes, and inadequate tissue adherence can affect the quality, reliability, and spatial resolution of MALDI images. We report a comparison of tissue mounting and washing methods that resulted in an optimized method using conductive carbon substrates that avoids thaw mounting or washing steps, minimizes protein delocalization, and prevents tissue detachment from the target surface. Application of this method to image ocular lens proteins of small vertebrate eyes demonstrates the improved methodology for imaging abundant crystallin protein products. This method was demonstrated for tissue sections from rat, mouse, and zebrafish lenses resulting in good-quality MALDI images with little to no delocalization. The images indicate, for the first time in mouse and zebrafish, discrete localization of crystallin protein degradation products resulting in concentric rings of distinct protein contents that may be responsible for the refractive index gradient of vertebrate lenses.
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15 MeSH Terms
Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction.
Walker AG, Wenthur CJ, Xiang Z, Rook JM, Emmitte KA, Niswender CM, Lindsley CW, Conn PJ
(2015) Proc Natl Acad Sci U S A 112: 1196-201
MeSH Terms: Animals, Behavior, Animal, Cognition, Fear, HEK293 Cells, Humans, Long-Term Synaptic Depression, Mice, Mice, Inbred ICR, Mice, Knockout, Prefrontal Cortex, Rats, Receptors, Metabotropic Glutamate
Show Abstract · Added January 20, 2015
Clinical studies have revealed that genetic variations in metabotropic glutamate receptor 3 (mGlu3) affect performance on cognitive tasks dependent upon the prefrontal cortex (PFC) and may be linked to psychiatric conditions such as schizophrenia, bipolar disorder, and addiction. We have performed a series of studies aimed at understanding how mGlu3 influences PFC function and cognitive behaviors. In the present study, we found that activation of mGlu3 can induce long-term depression in the mouse medial PFC (mPFC) in vitro. Furthermore, in vivo administration of a selective mGlu3 negative allosteric modulator impaired learning in the mPFC-dependent fear extinction task. The results of these studies implicate mGlu3 as a major regulator of PFC function and cognition. Additionally, potentiators of mGlu3 may be useful in alleviating prefrontal impairments associated with several CNS disorders.
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3 Members
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13 MeSH Terms