scholarly journals Endocannabinoid Levels in Ulcerative Colitis Patients Correlate With Clinical Parameters and Are Affected by Cannabis Consumption

2021 ◽  
Vol 12 ◽  
Author(s):  
Shelly Tartakover Matalon ◽  
Shahar Azar ◽  
David Meiri ◽  
Rivka Hadar ◽  
Alina Nemirovski ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Clinical Symptoms ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Beneficial Effects ◽  
Before And After ◽  
Bowel Diseases ◽  
Bowel Movements ◽  
Cannabis Consumption

BackgroundInflammatory bowel diseases (IBDs) are chronic, idiopathic, inflammatory, gastrointestinal disorders. The endocannabinoid system may have a role in the pathogenesis of IBD. We aimed to assess whether cannabis treatment influences endocannabinoids (eCBs) level and clinical symptoms of IBD patients.MethodsBlood samples and biopsies were taken from IBD patients treated by either cannabis or placebo for 8 weeks. Immunohistochemistry for N-acyl-phosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH) expression was done on colon biopsies, and sample levels of anandamide (AEA), eCB2-arachidonylglycerol (2-AG), arachidonic acid (AA), palmitoylethanolamine (PEA), and oleoylethanolamine (OEA) were measured in patient’s sera before and after cannabis treatment. Caco-2 cells were cultured with extracts of cannabis with/without tetrahydrocannabinol (THC) and their proteins extracted, and Western blotting for NAPE-PLD and FAAH expression was done.ResultsThirteen patients with Crohn’s disease (CD) and nine patients with ulcerative colitis (UC) were treated with cannabis. Seventeen patients with CD and 10 with UC served as placebo groups. In all CD patients, the levels of eCBs remained unaltered during the treatment period. In UC patients treated with placebo, but not in those treated with cannabis, the levels of PEA, AEA, and AA decreased significantly. The percent reduction in bowel movements was negatively correlated with changes observed in the circulating AEA and OEA, whereas improvement in quality of life was positively correlated with the levels of 2-AG. In the biopsies from UC patients, FAAH levels increased over the study period. In Caco-2 cells, both cannabis extracts increased NAPE-PLD levels but reduced FAAH expression levels.ConclusionOur study supports the notion that cannabis use affects eCB “tone” in UC patients and may have beneficial effects on disease symptoms in UC patients.

scholarly journals Elevated Brain Fatty Acid Amide Hydrolase Induces Depressive-Like Phenotypes in Rodent Models: A Review

2021 ◽  
Vol 22 (3) ◽  
pp. 1047
Author(s):  
Dorsa Rafiei ◽  
Nathan J. Kolla
Keyword(s):  
Depressive Symptoms ◽  
Fatty Acid ◽  
Animal Models ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Animal Models Of Depression ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Altered activity of fatty acid amide hydrolase (FAAH), an enzyme of the endocannabinoid system, has been implicated in several neuropsychiatric disorders, including major depressive disorder (MDD). It is speculated that increased brain FAAH expression is correlated with increased depressive symptoms. The aim of this scoping review was to establish the role of FAAH expression in animal models of depression to determine the translational potential of targeting FAAH in clinical studies. A literature search employing multiple databases was performed; all original articles that assessed FAAH expression in animal models of depression were considered. Of the 216 articles that were screened for eligibility, 24 articles met inclusion criteria and were included in this review. Three key findings emerged: (1) FAAH expression is significantly increased in depressive-like phenotypes; (2) genetic knockout or pharmacological inhibition of FAAH effectively reduces depressive-like behavior, with a dose-dependent effect; and (3) differences in FAAH expression in depressive-like phenotypes were largely localized to animal prefrontal cortex, hippocampus and striatum. We conclude, based on the animal literature, that a positive relationship can be established between brain FAAH level and expression of depressive symptoms. In summary, we suggest that FAAH is a tractable target for developing novel pharmacotherapies for MDD.

Estrogen stimulates arachidonoylethanolamide release from human endothelial cells and platelet activation

Blood ◽  
2002 ◽  
Vol 100 (12) ◽  
pp. 4040-4048 ◽  
Author(s):  
Mauro Maccarrone ◽  
Monica Bari ◽  
Natalia Battista ◽  
Alessandro Finazzi-Agrò
Keyword(s):  
Endothelial Cells ◽  
Fatty Acid Amide Hydrolase ◽  
Physiological Activity ◽  
Acid Amide ◽  
Adenosine Diphosphate ◽  
Human Endothelial Cells ◽  
Apparent Dissociation Constant ◽  
Surface Receptors ◽  
Beneficial Effects ◽  
Estrogen Binding

Estrogen replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, though the mechanism for this benefit remains unclear. Here we show that at physiological concentrations estrogen activates the anandamide membrane transporter of human endothelial cells and leads to rapid elevation of calcium (apparent within 5 minutes) and release of nitric oxide (within 15 minutes). These effects are mediated by estrogen binding to a surface receptor, which shows an apparent dissociation constant (Kd) of 9.4 ± 1.4 nM, a maximum binding (Bmax) of 356 ± 12 fmol × mg protein−1, and an apparent molecular mass of approximately 60 kDa. We also show that estrogen binding to surface receptors leads to stimulation of the anandamide-synthesizing enzyme phospholipase D and to inhibition of the anandamide-hydrolyzing enzyme fatty acid amide hydrolase, the latter effect mediated by 15-lipoxygenase activity. Because the endothelial transporter is shown to move anandamide across the cell membranes bidirectionally, taken together these data suggest that the physiological activity of estrogen is to stimulate the release, rather than the uptake, of anandamide from endothelial cells. Moreover, we show that anandamide released from estrogen-stimulated endothelial cells, unlike estrogen itself, inhibits the secretion of serotonin from adenosine diphosphate (ADP)–stimulated platelets. Therefore, it is suggested that the peripheral actions of anandamide could be part of the molecular events responsible for the beneficial effects of estrogen.

Role of the endocannabinoid system in the dorsal hippocampus in the cardiovascular changes and delayed anxiety-like effect induced by acute restraint stress in rats

2019 ◽  
Vol 33 (5) ◽  
pp. 606-614 ◽  
Author(s):  
Alice Hartmann ◽  
Aline Fassini ◽  
América Scopinho ◽  
Fernando MA Correa ◽  
Francisco S Guimarães ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Restraint Stress ◽  
Fatty Acid Amide Hydrolase ◽  
Dorsal Hippocampus ◽  
Cardiovascular Response ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Cardiovascular Responses ◽  
Fatty Acid Amide

Background: The dorsal hippocampus has a central role in modulating cardiovascular responses and behavioral adaptation to stress. The dorsal hippocampus also plays a key role in stress-associated mental disorders. The endocannabinoid system is widely expressed in the dorsal hippocampus and modulates defensive behaviors under stressful conditions. The endocannabinoid anandamide activates cannabinoid type 1 receptors and is metabolized by the fatty acid amide hydrolase enzyme. Aims: We sought to verify whether cannabinoid type 1 receptors modulate stress-induced cardiovascular changes, and if pharmacological fatty acid amide hydrolase inhibition in the dorsal hippocampus would prevent the cardiovascular responses and the delayed anxiogenic-like behavior evoked by restraint stress in rats via cannabinoid type 1 receptors. Methods: Independent groups received intra-dorsal-hippocampal injections of N-(piperidin-1yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-hpyrazole-3-carboxamide (AM251; cannabinoid type 1 receptor antagonist/inverse agonist, 10–300 pmol) and/or cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597; fatty acid amide hydrolase inhibitor, 10 pmol) before the restraint stress session. Cardiovascular response during restraint stress or later behavioral parameters were evaluated. Results: Acute restraint stress altered the cardiovascular response, characterized by increased heart rate and mean arterial pressure, as well as decreased tail cutaneous temperature. It also induced a delayed anxiogenic-like effect, evidenced by reduced open arm exploration in the elevated plus maze 24 h after stress. AM251 exacerbated the stress-induced cardiovascular responses after injection into the dorsal hippocampus. In contrast, local injection of URB597 prevented the cardiovascular response and the delayed (24 h) behavioral consequences of restraint stress, effects attenuated by pretreatment with AM251. Conclusion: Our data corroborate previous results indicating that the hippocampal endocannabinoid system modulates the outcome of stress exposure and suggest that this could involve modulation of the cardiovascular response during stress exposure.

scholarly journals The effect of high maternal linoleic acid on endocannabinoid signalling in rodent hearts

2019 ◽  
Vol 11 (6) ◽  
pp. 617-622 ◽  
Author(s):  
Simone L. Sleep ◽  
Nirajan Shrestha ◽  
James S. M. Cuffe ◽  
Olivia J. Holland ◽  
John P. Headrick ◽  
...  
Keyword(s):  
Linoleic Acid ◽  
Cell Viability ◽  
Mrna Expression ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
H9c2 Cell ◽  
Foetal Development ◽  
High Linoleic Acid

AbstractThe endocannabinoid system (ECS), modulated by metabolites of linoleic acid (LA), is important in regulating cardiovascular function. In pregnancy, LA is vital for foetal development. We investigated the effects of elevated LA in H9c2 cardiomyoblasts in vitro and of a high linoleic acid (HLA, 6.21%) or low linoleic acid (LLA, 1.44%) diet during pregnancy in maternal and offspring hearts. H9c2 cell viability was reduced following LA exposure at concentrations between 300 and 1000 µM. HLA diet decreased cannabinoid receptor type 2 (CB2) mRNA expression in foetal hearts from both sexes. However, HLA diet increased CB2 expression in maternal hearts. The mRNA expression of fatty acid amide hydrolase (FAAH) in foetal hearts was higher in females than in males irrespective of diet and N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) mRNA expression showed an interaction between diet and sex. Data indicate that a high LA diet alters cell viability and CB2 expression, potentially influencing cardiac function during pregnancy and development of the offspring’s heart.

Use of Synbiotics for Ulcerative Colitis Treatment

2020 ◽  
Vol 15 (3) ◽  
pp. 174-182 ◽  
Author(s):  
Marianna Roselli ◽  
Alberto Finamore
Keyword(s):  
Ulcerative Colitis ◽  
Gastrointestinal Tract ◽  
Intestinal Microbiota ◽  
Strong Impact ◽  
Beneficial Effects ◽  
System A ◽  
Bowel Diseases ◽  
Ulcerative Colitis Treatment ◽  
Inflammatory Bowel

Inflammatory bowel diseases, namely Crohn's disease and ulcerative colitis, are currently considered multifactorial pathologies in which various combined environmental factors act on genetic background, giving rise to chronic inflammation of the gastrointestinal tract. Ulcerative colitis is an inflammation of the colon caused by a dysregulated immune response to host intestinal microbiota in genetically susceptible subjects. Ulcerative colitis has a strong impact on patients' quality of life, as well as high costs for the health-care system. A great interest on the role of intestinal microbiota modulation in ulcerative colitis is emerging. Several studies have shown an improvement of inflammatory markers and symptoms in ulcerative colitis patients through treatments with probiotics and prebiotics separately. Despite the low number of studies on the treatment of ulcerative colitis by specific strains of probiotics plus selected prebiotics, i.e. synbiotics, the results are promising, even if discordant. The mechanism of action in synbiotics supplementation is still unclear and needs more investigation, although there is a large number of data indicating that the synergism between probiotics and prebiotics favours the survival and implantation of probiotics into the gastrointestinal tract with beneficial effects on human health by modulating the inflammatory response and gut microbiota composition. The aim of this minireview is to describe the main in vitro, animal and human studies performed up to now, that have used synbiotics to treat ulcerative colitis, and to highlight limitations and future perspectives.

Fatty Acid Amide Hydrolase Inhibitors from Virtual Screening of the Endocannabinoid System

2006 ◽  
Vol 49 (15) ◽  
pp. 4650-4656 ◽  
Author(s):  
Susanna M. Saario ◽  
Antti Poso ◽  
Risto O. Juvonen ◽  
Tomi Järvinen ◽  
Outi M. H. Salo-Ahen
Keyword(s):  
Fatty Acid ◽  
Virtual Screening ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

scholarly journals Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

2012 ◽  
Vol 9 (4) ◽  
pp. 801-813 ◽  
Author(s):  
Vinogran Naidoo ◽  
David A. Karanian ◽  
Subramanian K. Vadivel ◽  
Johnathan R. Locklear ◽  
JodiAnne T. Wood ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Monoacylglycerol Lipase ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

scholarly journals UPLC-MS/MS Method for Analysis of Endocannabinoid and Related Lipid Metabolism in Mouse Mucosal Tissue

2021 ◽  
Vol 12 ◽  
Author(s):  
Mark B. Wiley ◽  
Pedro A. Perez ◽  
Donovan A. Argueta ◽  
Bryant Avalos ◽  
Courtney P. Wood ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
The Body ◽  
Mucosal Tissues ◽  
Degradative Enzymes ◽  
Health And Disease ◽  
Amide Hydrolase

The endocannabinoid system is expressed in cells throughout the body and controls a variety of physiological and pathophysiological functions. We describe robust and reproducible UPLC-MS/MS-based methods for analyzing metabolism of the endocannabinoids, 2-arachidonoyl-sn-glycerol and arachidonoyl ethanolamide, and related monoacylglycerols (MAGs) and fatty acid ethanolamides (FAEs), respectively, in mouse mucosal tissues (i.e., intestine and lung). These methods are optimized for analysis of activity of the MAG biosynthetic enzyme, diacylglycerol lipase (DGL), and MAG degradative enzymes, monoacylglycerol lipase (MGL) and alpha/beta hydrolase domain containing-6 (ABHD6). Moreover, we describe a novel UPLC-MS/MS-based method for analyzing activity of the FAE degradative enzyme, fatty acid amide hydrolase (FAAH), that does not require use of radioactive substrates. In addition, we describe in vivo pharmacological methods to inhibit MAG biosynthesis selectively in the mouse small-intestinal epithelium. These methods will be useful for profiling endocannabinoid metabolism in rodent mucosal tissues in health and disease.

scholarly journals CRISPR interference at the FAAH-OUT genomic region reduces FAAH expression

2019 ◽  
Author(s):  
Hajar Mikaeili ◽  
Charlix Yeung ◽  
Abdella M Habib ◽  
John N Wood ◽  
Andrei L Okorokov ◽  
...  
Keyword(s):  
Gene Editing ◽  
Clinical Symptoms ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Regulatory Elements ◽  
Human Cell Line ◽  
Genomic Region ◽  
Chromosome 1 ◽  
Bioactive Lipids ◽  
Post Operative Nausea

AbstractFAAH-OUT encodes a putative long non-coding RNA which is located next to the FAAH gene on human chromosome 1. Recently an ~8 kb microdeletion, that removes upstream regulatory elements and the first 2 exons of FAAH-OUT, was reported in a pain insensitive patient (PFS) with additional clinical symptoms including a happy, non-anxious disposition, fast wound healing, fear and memory deficits, and significant post-operative nausea and vomiting induced by morphine. PFS also carries a hypomorphic SNP in FAAH that significantly reduces the activity of the encoded fatty-acid amide hydrolase enzyme. The FAAH and FAAH-OUT mutations identified in PFS result in elevated levels of anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamine (OEA) measured in peripheral blood. These bioactive lipids, which are normally degraded by FAAH, have diverse biological functions including known roles in pain pathways.Here we report the first mechanistic insights into how the FAAH-OUT microdeletion affects FAAH function. Gene editing in a human cell line to mimic the FAAH-OUT microdeletion observed in PFS results in reduced expression of FAAH. Furthermore, CRISPRi experiments targeting the promoter region of FAAH-OUT or a short highly evolutionarily conserved element in the first intron of FAAH-OUT also result in reduced expression of FAAH. These experiments confirm the importance of FAAH-OUT and specific genomic elements within the ~8 kb microdeleted sequence to normal FAAH expression. Our results also highlight the potential of CRISPRi and gene editing strategies that target the FAAH-OUT region for the development of novel FAAH-based analgesic and anxiolytic therapies.

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