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R Bonsale, R Seyed Sharifi, E Dirandeh, N Hedayat, A Mojtahedin, M Ghorbanalinia, A Abolghasemi
The objective of this study was to consider endocannabinoid system as inflammatory markers in bovine endometrium to better understand the role of this system in regulating many of the functions that are related to inflammatory condition. At day 26 post-partum, fourteen cows were divided into two groups depending on the inflammatory condition: 1- subclinical endometritis (n = 7, with purulent or mucopurulent uterine discharge detectable in the vagina) and 2- healthy (n = 7, No (muco)) purulent discharge...
March 14, 2018: Reproduction in Domestic Animals, Zuchthygiene
Roberto Colangeli, Massimo Pierucci, Arcangelo Benigno, Giuseppe Campiani, Stefania Butini, Giuseppe Di Giovanni
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
March 12, 2018: Scientific Reports
Jenny L Wilkerson, Zachary A Curry, Pamela D Kinlow, Brittany L Mason, Ku-Lung Hsu, Mario van der Stelt, Benjamin F Cravatt, Aron H Lichtman
A great need exists for the identification of new effective analgesics to treat sustained pain. However, most preclinical nociceptive assays measure behavioral responses evoked by noxious stimuli (i.e., pain-stimulated behavior), which presents a challenge to distinguish between motor impairing and antinociceptive effects of drugs. Here, we demonstrate that chronic constriction injury of the sciatic nerve (CCI) elicits common pain-stimulated responses (i.e., mechanical allodynia and thermal hyperalgesia) as well as reduces marble burying/digging behaviors that occur during the early stages of the neuropathy and resolve within one week...
March 8, 2018: Pain
Sharon Fidelman, Tomer Mizrachi Zer-Aviv, Rachel Lange, Cecilia J Hillard, Irit Akirav
Activating the endocannabinoid system has become a major focus in the search for novel therapeutics for anxiety and deficits in fear extinction, two defining features of PTSD. We examined whether chronic treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.2, 0.3, 0.4 mg/kg, i.p.) or the CB1/2 receptor agonist WIN55,212-2 (0.25, 0.5 mg/kg, i.p.) injected for 3 weeks to rats exposed to the shock and reminders model of PTSD would attenuate post-stress symptoms and affect basolateral amygdala (BLA) and CA1 CB1 receptors...
March 5, 2018: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Manoela V Fogaça, Alline C de Campos, Ludmila D Coelho, Ronald S Duman, Francisco S Guimarães
Repeated injections of cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, attenuate the anxiogenic effects induced by Chronic Unpredictable Stress (CUS). The specific mechanisms remain to be fully understood but seem to involve adult hippocampal neurogenesis and recruitment of endocannabinoids. Here we investigated for the first time if the behavioral and pro-neurogenic effects of CBD administered concomitant the CUS procedure (14 days) are mediated by CB1 , CB2 or 5HT1A receptors, as well as CBD effects on dendritic remodeling and on intracellular/synaptic signaling (fatty acid amide hydrolase - FAAH, Akt, GSK3β and the synaptic proteins Synapsin Ia/b, mGluR1 and PSD95)...
March 3, 2018: Neuropharmacology
Nóra Zákány, Attila Oláh, Arnold Markovics, Erika Takács, Andrea Aranyász, Simon Nicolussi, Fabiana Piscitelli, Marco Allarà, Ágnes Pór, Ilona Kovács, Christos C Zouboulis, Jürg Gertsch, Vincenzo Di Marzo, Tamás Bíró, Tamás Szabó
We have previously shown that i) endocannabinoids (eCB; e.g. anandamide [AEA]) are involved in the maintenance of homeostatic sebaceous lipid production (SLP) in human sebaceous glands (SG); and ii) eCB treatment dramatically increases SLP. Here, we aimed to investigate the expression of the major eCB synthesizing and degrading enzymes, and to study the effects of eCB uptake inhibitors on human SZ95 sebocytes, thus exploring the role of the putative eCB membrane transporter (EMT), which has been hypothesized to facilitate the cellular uptake and subsequent degradation of eCBs...
February 28, 2018: Journal of Investigative Dermatology
Or Burstein, Noa Shoshan, Ravid Doron, Irit Akirav
Posttraumatic stress disorder (PTSD) is a debilitating condition highly comorbid with depression. The endocannabinoid (eCB) system and brain-derived neurotrophic factor (BDNF) are suggestively involved in both disorders. We examined whether cannabinoids can prevent the long-term depressive-like symptoms induced by exposure to the shock and situational reminders (SRs) model of PTSD. The CB1/2 receptor agonist WIN55,212-2 (0.5 mg/kg; i.p.), the fatty acid hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg, i.p.) or vehicle were administered 2 h after severe shock...
February 16, 2018: Progress in Neuro-psychopharmacology & Biological Psychiatry
John Hamilton, Matthew Marion, Antonio Figueiredo, Brendan H Clavin, Dale Deutsch, Martin Kaczocha, Samir Haj-Dahmane, Panayotis K Thanos
Genetic and pharmacological manipulation of endocannabinoid (eCB) signaling has previously been shown to have an important role on the rewarding properties of drugs of abuse, including cocaine. Recently, fatty acid binding proteins (FABPs) have been proposed as intracellular transporters of the endocannabinoid anandamide (AEA) as well as other bioactive lipids to their catabolic enzyme, fatty acid amide hydrolase (FAAH). The role of these transporters in modulating the brains reward system has yet to be investigated...
February 19, 2018: Synapse
V E Tóth, Á Fehér, J Németh, I Gyertyán, Z S Zádori, K Gyires
Previous findings showed that inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), degrading enzymes of anandamide (2-AEA) and 2-arachidonoylglycerol (2-AG), reduced the nonsteroidal anti-inflammatory drug-induced gastric lesions. The present study aimed to investigate: i./whether central or peripheral mechanism play a major role in the gastroprotective effect of inhibitors of FAAH, MAGL and AEA uptake, ii./which peripheral mechanism(s) may play a role in mucosal protective effect of FAAH, MAGL and uptake inhibitors...
February 10, 2018: Brain Research Bulletin
Avery L McIntosh, Gregory G Martin, Huan Huang, Danilo Landrock, Ann B Kier, Friedhelm Schroeder
Phytocannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC), bind and activate cannabinoid receptors (CB)-thereby piggy-backing on the same pathway endogenous endocannabinoids (EC). The recent discovery that liver fatty acid binding protein-1 (FABP1) is the major cytosolic chaperone protein with high affinity for both Δ9-THC and EC suggests that Δ9-THC may alter hepatic EC levels. Therefore, the impact of Δ9-THC or EC treatment on endogenous ECs such as N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) levels was examined in cultured primary mouse hepatocytes from wild-type (WT) and liver fatty acid binding protein-1 (Fabp1) gene ablated (LKO) mice...
February 5, 2018: Journal of Lipid Research
Judit Lazary, Nora Eszlari, Gabriella Juhasz, Gyorgy Bagdy
BACKGROUND: Accumulating data confirmed that the endocannabinoid system (ECS) is involved in the regulation of stress response and emotional processes, therefore ECS became an important pharmacological target as a potential anxiolytic. Although unequivocal data from animal studies confirmed the relevancy of the ECS in anxious phenotype, human genetic data are poorly available in the literature in this field. In the presented studies we tested possible associations between anxious phenotype and the cannabinoid receptor 1 and the fatty acid amide hydrolase gene polymorphisms...
December 2017: Neuropsychopharmacologia Hungarica
Florian M Dato, Andreas Maaßen, Bernd Goldfuß, Markus Pietsch
Fatty acid amide hydrolase (FAAH) is involved in many human diseases, particularly cancer, pain and inflammation as well as neurological, metabolic and cardiovascular disorders. Therefore, FAAH is an attractive target for the development of low-molecular-weight inhibitors as therapeutics, which requires robust assays that can be used for high-throughput screening (HTS) of compound libraries. Here, we report the development of a fluorometric assay based on FAAH's ability to effectively hydrolyze medium-chain fatty acid amides, introducing N-decanoyl-substituted 5-amino-2-methoxypyridine (D-MAP) as new amide substrate...
January 30, 2018: Analytical Biochemistry
Guy Griebel, Jeanne Stemmelin, Mati Lopez-Grancha, Valérie Fauchey, Franck Slowinski, Philippe Pichat, Gihad Dargazanli, Ahmed Abouabdellah, Caroline Cohen, Olivier E Bergis
Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids...
February 5, 2018: Scientific Reports
Sean D Kodani, Saavan Bhakta, Sung Hee Hwang, Svetlana Pakhomova, Marcia E Newcomer, Christophe Morisseau, Bruce D Hammock
Multi-target inhibitors have become increasing popular as a means to leverage the advantages of poly-pharmacology while simplifying drug delivery. Here, we describe dual inhibitors for soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH), two targets known to synergize when treating inflammatory and neuropathic pain. The structure activity relationship (SAR) study described herein initially started with t-TUCB (trans-4-[4-(3-trifluoromethoxyphenyl-l-ureido)-cyclohexyloxy]-benzoic acid), a potent sEH inhibitor that was previously shown to weakly inhibit FAAH...
January 4, 2018: Bioorganic & Medicinal Chemistry Letters
Jakub Mlost, Magdalena Kostrzewa, Natalia Malek, Katarzyna Starowicz
Osteoarthritis (OA) is a joint disease in which cartilage degenerates as a result of mechanical and biochemical changes. The main OA symptom is chronic pain involving both peripheral and central mechanisms of nociceptive processing. Our previous studies have implicated the benefits of dual- over single-acting compounds interacting with the endocannabinoid system (ECS) in OA treatment. In the present study, we focused on the specific molecular alterations associated with pharmacological treatment. OA was induced in Wistar rats by intra-articular injection of 3 mg of monoiodoacetate (MIA)...
January 24, 2018: International Journal of Molecular Sciences
Francisco Espejo-Porras, Javier Fernández-Ruiz, Eva de Lago
OBJECTIVE: We have investigated the endocannabinoid system in the motor cortex of motor neuron disease (MND) patients. METHODS: Post-mortem samples from MND patients and controls were used for immunostaining and/or Western blotting analysis of endocannabinoid elements. RESULTS: We did not find any evidence of neuronal losses in the motor cortex of MND patients, but elevations in glial markers Iba-1 and GFAP were evident. We found no changes in FAAH and MAGL enzymes and in the CB1 receptor, which correlated with the lack of cortical neuron death...
January 15, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Michael C Goodman, Shu Xu, Carol A Rouzer, Surajit Banerjee, Kebreab Ghebreselasie, Marco Migliore, Daniele Piomelli, Lawrence J Marnett
The cyclooxygenases COX-1 and COX-2 oxygenate arachidonic acid (AA) to prostaglandin H2 (PGH2). COX-2 also oxygenates the endocannabinoids, 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA), to the corresponding PGH2 analogs. Both enzymes are targets of nonsteroidal anti-inflammatory drugs (NSAIDs), but NSAID-mediated COX inhibition is associated with gastrointestinal toxicity. One potential strategy to counter this toxicity is to also inhibit fatty acid amide hydrolase (FAAH), which hydrolyzes bioactive fatty acid ethanolamides (FAEs) into fatty acids and ethanolamine...
January 11, 2018: Journal of Biological Chemistry
Mireille Alhouayek, Linda Rankin, Sandra Gouveia-Figueira, Christopher J Fowler
BACKGROUND AND PURPOSE: Endocannabinoids and related N-acylethanolamines (NAEs) are involved in regulation of gut function, but relatively little is known as to whether inflammatory cytokines such as interferon γ (IFNγ) affect their levels. We have investigated this in vitro using T84 colon cancer cells, which when cultured in monolayers differentiate to form adult colonic crypt-like cells with excellent permeability barrier properties. EXPERIMENTAL APPROACH: NAE levels were determined by ultra-performance liquid chromatography-tandem mass spectrometric analysis...
January 3, 2018: British Journal of Pharmacology
Randall G Krug, Han B Lee, Louis Y El Khoury, Ashley N Sigafoos, Morgan O Petersen, Karl J Clark
The ability to orchestrate appropriate physiological and behavioral responses to stress is important for survival, and is often dysfunctional in neuropsychiatric disorders that account for leading causes of global disability burden. Numerous studies have shown that the endocannabinoid neurotransmitter system is able to regulate stress responses and could serve as a therapeutic target for the management of these disorders. We used quantitative reverse transcriptase-polymerase chain reactions to show that genes encoding enzymes that synthesize (abhd4, gde1, napepld), enzymes that degrade (faah, faah2a, faah2b), and receptors that bind (cnr1, cnr2, gpr55-like) endocannabinoids are expressed in zebrafish (Danio rerio)...
2018: PloS One
Xiaofei Sun, Alexandra Tavenier, Wenbo Deng, Emma Leishman, Heather B Bradshaw, Sudhansu K Dey
Premature decidual senescence is a contributing factor to preterm birth. Fatty acid amide hydrolase mutant females (Faah-/-) with higher endocannabinoid levels are also more susceptible to preterm birth upon lipopolysaccharide (LPS) challenge due to enhanced decidual senescence; this is associated with mitogen-activated protein kinase p38 activation. Previous studies have shown that mechanistic target of rapamycin complex 1 (mTORC1) contributes to decidual senescence and promotes the incidence of preterm birth...
February 1, 2018: Biology of Reproduction
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