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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
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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3 Members
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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
Ketamine and MAG Lipase Inhibitor-Dependent Reversal of Evolving Depressive-Like Behavior During Forced Abstinence From Alcohol Drinking.
Holleran KM, Wilson HH, Fetterly TL, Bluett RJ, Centanni SW, Gilfarb RA, Rocco LE, Patel S, Winder DG
(2016) Neuropsychopharmacology 41: 2062-71
MeSH Terms: Affect, Alcohol Drinking, Animals, Behavior, Animal, Benzodioxoles, Depression, Endocannabinoids, Ethanol, Excitatory Amino Acid Antagonists, Female, Ketamine, Mice, Inbred C57BL, Monoacylglycerol Lipases, Piperidines
Show Abstract · Added March 14, 2018
Although alcoholism and depression are highly comorbid, treatment options that take this into account are lacking, and mouse models of alcohol (ethanol (EtOH)) intake-induced depressive-like behavior have not been well established. Recent studies utilizing contingent EtOH administration through prolonged two-bottle choice access have demonstrated depression-like behavior following EtOH abstinence in singly housed female C57BL/6J mice. In the present study, we found that depression-like behavior in the forced swim test (FST) is revealed only after a protracted (2 weeks), but not acute (24 h), abstinence period. No effect on anxiety-like behavior in the EPM was observed. Further, we found that, once established, the affective disturbance is long-lasting, as we observed significantly enhanced latencies to approach food even 35 days after ethanol withdrawal in the novelty-suppressed feeding test (NSFT). We were able to reverse affective disturbances measured in the NSFT following EtOH abstinence utilizing the N-methyl D-aspartate receptor (NMDAR) antagonist and antidepressant ketamine but not memantine, another NMDAR antagonist. Pretreatment with the monoacylglycerol (MAG) lipase inhibitor JZL-184 also reduced affective disturbances in the NSFT in ethanol withdrawn mice, and this effect was prevented by co-administration of the CB1 inverse agonist rimonabant. Endocannabinoid levels were decreased within the BLA during abstinence compared with during drinking. Finally, we demonstrate that the depressive behaviors observed do not require a sucrose fade and that this drinking paradigm may favor the development of habit-like EtOH consumption. These data could set the stage for developing novel treatment approaches for alcohol-withdrawal-induced mood and anxiety disorders.
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2 Members
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14 MeSH Terms
Dual targeting of EWS-FLI1 activity and the associated DNA damage response with trabectedin and SN38 synergistically inhibits Ewing sarcoma cell growth.
Grohar PJ, Segars LE, Yeung C, Pommier Y, D'Incalci M, Mendoza A, Helman LJ
(2014) Clin Cancer Res 20: 1190-203
MeSH Terms: Animals, Antineoplastic Agents, Camptothecin, Cell Line, Tumor, DNA Breaks, Double-Stranded, DNA Damage, Dioxoles, Disease Models, Animal, Doxorubicin, Drug Resistance, Neoplasm, Drug Synergism, Exodeoxyribonucleases, Female, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, Irinotecan, Mice, Oncogene Proteins, Fusion, Phenotype, Proto-Oncogene Protein c-fli-1, RNA Interference, RNA, Small Interfering, RNA-Binding Protein EWS, RecQ Helicases, Sarcoma, Ewing, Tetrahydroisoquinolines, Trabectedin, Werner Syndrome Helicase, Xenograft Model Antitumor Assays
Show Abstract · Added March 5, 2014
PURPOSE - The goal of this study is to optimize the activity of trabectedin for Ewing sarcoma by developing a molecularly targeted combination therapy.
EXPERIMENTAL DESIGN - We have recently shown that trabectedin interferes with the activity of EWS-FLI1 in Ewing sarcoma cells. In this report, we build on this work to develop a trabectedin-based combination therapy with improved EWS-FLI1 suppression that also targets the drug-associated DNA damage to Ewing sarcoma cells.
RESULTS - We demonstrate by siRNA experiments that EWS-FLI1 drives the expression of the Werner syndrome protein (WRN) in Ewing sarcoma cells. Because WRN-deficient cells are known to be hypersensitive to camptothecins, we utilize trabectedin to block EWS-FLI1 activity, suppress WRN expression, and selectively sensitize Ewing sarcoma cells to the DNA-damaging effects of SN38. We show that trabectedin and SN38 are synergistic, demonstrate an increase in DNA double-strand breaks, an accumulation of cells in S-phase and a low picomolar IC50. In addition, SN38 cooperates with trabectedin to augment the suppression of EWS-FLI1 downstream targets, leading to an improved therapeutic index in vivo. These effects translate into the marked regression of two Ewing sarcoma xenografts at a fraction of the dose of camptothecin used in other xenograft studies.
CONCLUSIONS - These results provide the basis and rationale for translating this drug combination to the clinic. In addition, the study highlights an approach that utilizes a targeted agent to interfere with an oncogenic transcription factor and then exploits the resulting changes in gene expression to develop a molecularly targeted combination therapy.
©2013 AACR
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1 Members
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30 MeSH Terms
Bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone antagonize methamphetamine-induced efflux of dopamine according to their potencies as dopamine uptake inhibitors: implications for the treatment of methamphetamine dependence.
Simmler LD, Wandeler R, Liechti ME
(2013) BMC Res Notes 6: 220
MeSH Terms: Amphetamine-Related Disorders, Benzodioxoles, Biological Transport, Bupropion, Dopamine, Humans, Methamphetamine, Methylphenidate, Pyrrolidines
Show Abstract · Added August 3, 2013
BACKGROUND - Methamphetamine-abuse is a worldwide health problem for which no effective therapy is available. Inhibition of methamphetamine-induced transporter-mediated dopamine (DA) release could be a useful approach to treat methamphetamine-addiction. We assessed the potencies of bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone (MDPV) to block DA uptake or to inhibit methamphetamine-induced DA release in HEK-293 cells expressing the human DA transporter.
FINDINGS - Bupropion, methylphenidate, and MDPV inhibited methamphetamine-induced DA release with relative potencies corresponding to their potencies to block DA uptake (potency ranks: MDPV > methylphenidate > bupropion).
CONCLUSIONS - Bupropion and methylphenidate antagonize the effects of methamphetamine in vitro and may be potential candidates for the treatment of stimulant addiction. However, drugs that very potently antagonize the effect of methamphetamine are likely to also exhibit considerable abuse liability (MDPV > methylphenidate > bupropion).
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9 MeSH Terms
CaMKII regulates diacylglycerol lipase-α and striatal endocannabinoid signaling.
Shonesy BC, Wang X, Rose KL, Ramikie TS, Cavener VS, Rentz T, Baucum AJ, Jalan-Sakrikar N, Mackie K, Winder DG, Patel S, Colbran RJ
(2013) Nat Neurosci 16: 456-63
MeSH Terms: Animals, Arachidonic Acids, Benzodioxoles, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Corpus Striatum, Endocannabinoids, Gene Knockdown Techniques, Glycerides, HEK293 Cells, Humans, Lipoprotein Lipase, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Piperidines, Signal Transduction
Show Abstract · Added July 2, 2013
The endocannabinoid 2-arachidonoylglycerol (2-AG) mediates activity-dependent depression of excitatory neurotransmission at central synapses, but the molecular regulation of 2-AG synthesis is not well understood. Here we identify a functional interaction between the 2-AG synthetic enzyme diacylglycerol lipase-α (DGLα) and calcium/calmodulin dependent protein kinase II (CaMKII). Activated CaMKII interacted with the C-terminal domain of DGLα, phosphorylated two serine residues and inhibited DGLα activity. Consistent with an inhibitory role for CaMKII in 2-AG synthesis, in vivo genetic inhibition of CaMKII increased striatal DGL activity and basal levels of 2-AG, and CaMKII inhibition augmented short-term retrograde endocannabinoid signaling at striatal glutamatergic synapses. Lastly, blockade of 2-AG breakdown using concentrations of JZL-184 that have no effect in wild-type mice produced a hypolocomotor response in mice with reduced CaMKII activity. These findings provide mechanistic insights into the molecular regulation of striatal endocannabinoid signaling with implications for physiological control of motor function.
0 Communities
5 Members
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17 MeSH Terms
Prospects and challenges for the development of new therapies for Ewing sarcoma.
Grohar PJ, Helman LJ
(2013) Pharmacol Ther 137: 216-24
MeSH Terms: Antineoplastic Agents, Bone Neoplasms, Camptothecin, Clinical Trials as Topic, Dioxoles, Epigenesis, Genetic, Humans, Molecular Targeted Therapy, Poly(ADP-ribose) Polymerase Inhibitors, Sarcoma, Ewing, Somatomedins, Tetrahydroisoquinolines, Trabectedin
Show Abstract · Added September 3, 2013
The Ewing sarcoma family of tumors or Ewing sarcoma (ES) is the second most common malignant bone tumor of childhood. The prognosis for localized Ewing sarcoma has improved through the development of intense multimodal therapy over the past several decades. Unfortunately, patients with recurrent or metastatic disease continue to have a poor prognosis. Therefore, a number of complementary approaches are being developed in both the preclinical and clinical arenas to improve these outcomes. In this review, we will discuss efforts to directly target the biologic drivers of this disease and relate these efforts to the experience with several different agents both in the clinic and under development. We will review the data for compounds that have shown excellent activity in the clinic, such as the camptothecins, and summarize the biological data that supports this activity. In addition, we will review the clinical experience with IGF1 targeted agents, ET-743 and epigenetically targeted therapies, the substantial amount of literature that supports their activity in Ewing sarcoma and the challenges remaining translating these therapies to the clinic. Finally, we will highlight recent work aimed at directly targeting the EWS-FLI1 transcription factor with small molecules in Ewing tumors.
Copyright © 2012 Elsevier Inc. All rights reserved.
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2 Members
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13 MeSH Terms
Reversible gating of endocannabinoid plasticity in the amygdala by chronic stress: a potential role for monoacylglycerol lipase inhibition in the prevention of stress-induced behavioral adaptation.
Sumislawski JJ, Ramikie TS, Patel S
(2011) Neuropsychopharmacology 36: 2750-61
MeSH Terms: Adaptation, Psychological, Amygdala, Animals, Anxiety Disorders, Arachidonic Acids, Benzodioxoles, Cannabinoid Receptor Modulators, Chronic Disease, Disease Models, Animal, Endocannabinoids, Glycerides, Male, Mice, Mice, Inbred ICR, Monoacylglycerol Lipases, Organ Culture Techniques, Piperidines, Stress, Psychological
Show Abstract · Added January 20, 2015
Chronic stress is the primary environmental risk factor for the development and exacerbation of affective disorders, thus understanding the neuroadaptations that occur in response to stress is a critical step in the development of novel therapeutics for depressive and anxiety disorders. Brain endocannabinoid (eCB) signaling is known to modulate emotional behavior and stress responses, and levels of the eCB 2-arachidonoylglycerol (2-AG) are elevated in response to chronic homotypic stress exposure. However, the role of 2-AG in the synaptic and behavioral adaptations to chronic stress is poorly understood. Here, we show that stress-induced development of anxiety-like behavior is paralleled by a transient appearance of low-frequency stimulation-induced, 2-AG-mediated long-term depression at GABAergic synapses in the basolateral amygdala, a key region involved in motivation, affective regulation, and emotional learning. This enhancement of 2-AG signaling is mediated, in part, via downregulation of the primary 2-AG-degrading enzyme monoacylglycerol lipase (MAGL). Acute in vivo inhibition of MAGL had little effect on anxiety-related behaviors. However, chronic stress-induced anxiety-like behavior and emergence of long-term depression of GABAergic transmission was prevented by chronic MAGL inhibition, likely via an occlusive mechanism. These data indicate that chronic stress reversibly gates eCB synaptic plasticity at inhibitory synapses in the amygdala, and in vivo augmentation of 2-AG levels prevents both behavioral and synaptic adaptations to chronic stress.
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1 Members
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18 MeSH Terms
Ecteinascidin 743 interferes with the activity of EWS-FLI1 in Ewing sarcoma cells.
Grohar PJ, Griffin LB, Yeung C, Chen QR, Pommier Y, Khanna C, Khan J, Helman LJ
(2011) Neoplasia 13: 145-53
MeSH Terms: Antineoplastic Agents, Alkylating, Bone Neoplasms, Cell Line, Tumor, Child, DAX-1 Orphan Nuclear Receptor, Dioxoles, Europe, Gene Expression Regulation, Neoplastic, Humans, Oncogene Proteins, Fusion, Promoter Regions, Genetic, Proto-Oncogene Protein c-fli-1, RNA-Binding Protein EWS, RNA-Binding Protein FUS, Sarcoma, Sarcoma, Ewing, Tetrahydroisoquinolines, Trabectedin, Transcription Factor CHOP
Show Abstract · Added September 3, 2013
ET-743 (trabectedin; Yondelis) is approved in Europe for the treatment of soft tissue sarcomas. Emerging phase 1 and 2 clinical data have shown high response rates in myxoid liposarcoma in part owing to the inhibition of the FUS-CHOP transcription factor. In this report, we show that modulation of specific oncogenic transcription factors by ET-743 may extend to other tumor types. We demonstrate that, among a panel of pediatric sarcomas, Ewing sarcoma family of tumors (ESFTs) cell lines bearing the EWS-FLI1 transcription factor are the most sensitive to treatment with ET-743 compared with osteosarcoma, rhabdomyosarcoma, and synovial sarcoma. We show that ET-743 reverses a gene signature of induced downstream targets of EWS-FLI1 in two different ESFT cell lines (P = .001). In addition, ET-743 directly suppresses the promoter activity of a known EWS-FLI1 downstream target NR0B1 luciferase reporter construct without changing the activity of a constitutively active control in ESFT cells. Furthermore, the effect is specific to EWS-FLI1, as forced expression of EWS-FLI1 in a cell type that normally lacks this fusion protein, HT1080 cells, induces the same NR0B1 promoter, but this activation is completely blocked by ET-743 treatment. Finally, we used gene set enrichment analysis to confirm that other mechanisms of ET-743 are active in ESFT cells. These results suggest a particular role for ET-743 in the treatment of translocation-positive tumors. In addition, the modulation of EWS-FLI1 makes it a novel targeting agent for ESFT and suggests that further development of this compound for the treatment of ESFT is warranted.
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19 MeSH Terms