Tag Archives: fatty acid amide hydrolase (FAAH)

Palmitoylethanolamide: From endogenous cannabimimetic substance to innovative medicine for the treatment of cannabis dependence.

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“Palmitoylethanolamide (PEA) is a fatty acid amide showing some pharmacodynamic similarities with Δ9-tetrahydrocannabinol, the principal psychoactive compound present in the cannabis plant.

Like Δ9-tetrahydrocannabinol, PEA can produce a direct or indirect activation of cannabinoid receptors.

 Furthermore, it acts as an agonist at TRPV1 receptor.

The hypothesis is that PEA has anti-craving effects in cannabis dependent patients, is efficacious in the treatment of withdrawal symptoms, produces a reduction of cannabis consumption and is effective in the prevention of cannabis induced neurotoxicity and neuro-psychiatric disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/23896215

The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity.

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“Crohn’s disease and ulcerative colitis are two major forms of inflammatory bowel diseases (IBD), which are chronic inflammatory disorders of the gastrointestinal tract. These pathologies are currently under investigation to both unravel their etiology and find novel treatments.

Anandamide and 2-arachidonoylglycerol are endogenous bioactive lipids that bind to and activate the cannabinoid receptors, and together with the enzymes responsible for their biosynthesis and degradation [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)] constitute the endocannabinoid system (ECS).

The ECS is implicated in gut homeostasis, modulating gastrointestinal motility, visceral sensation, and inflammation, as well as being recently implicated in IBD pathogenesis.

Numerous subsequent studies investigating the effects of cannabinoid agonists and endocannabinoid degradation inhibitors in rodent models of IBD have identified a potential therapeutic role for the ECS.”

http://www.ncbi.nlm.nih.gov/pubmed/22917662

Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1 and CB2 receptors.

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“The endocannabinoid (EC) system mediates protection against intestinal inflammation. In this study, we investigated the effects of blocking EC degradation or cellular reuptake in experimental colitis in mice…

 In conclusion, drugs targeting EC degradation offer therapeutic potential in the treatment of inflammatory bowel diseases. Furthermore, reduction of FAAH mRNA expression is involved in the pathophysiological response to colitis.”

http://www.ncbi.nlm.nih.gov/pubmed/18493729

The role of fatty acid hydrolase gene variants in inflammatory bowel disease.

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“Recent studies suggest a role for the endocannabinoid system, including fatty acid amide hydrolase (FAAH), in intestinal inflammation.

AIM:

To analyse FAAH expression and the FAAH 385 C/A (p.Pro129Thr; rs324420) single nucleotide polymorphism (SNP) in-patients with Crohn’s disease (CD) and ulcerative colitis (UC).

CONCLUSION:

The FAAH p.Pro129Thr polymorphism may modulate the CD phenotype.”

http://www.ncbi.nlm.nih.gov/pubmed/19053981

Inhibition of endocannabinoid degradation in experimental endotoxemia reduces leukocyte adhesion and improves capillary perfusion in the gut.

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“Changes in leukocyte-endothelial and microvascular perfusion are hallmark events in inflammation. Thus, protection of the intestinal microcirculation represents a pivotal therapeutic target in systemic inflammation and sepsis.

The endocannabinoid system (ECS) modulates a number of critical homeostatic functions and has been associated with anti-inflammatory responses. Our study aimed to examine intestinal leukocyte adhesion and capillary perfusion following selective inhibition of the endocannabinoid degradation enzyme, fatty acid amide hydrolase (FAAH), in experimental sepsis (endotoxemia).

Conclusions: FAAH inhibition prevents the LPS-induced increase in leukocyte adhesion and improves the capillary perfusion of the gut. This might be mediated in part by CB2R activation.

Our study encourages further investigation into the therapeutic potential of drugs targeting the ECS in sepsis.”

More: http://www.ncbi.nlm.nih.gov/pubmed/23382309

The association of N-palmitoylethanolamine with the FAAH inhibitor URB597 impairs melanoma growth through a supra-additive action.

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“The incidence of melanoma is considerably increasing worldwide. Frequent failing of classical treatments led to development of novel therapeutic strategies aiming at managing advanced forms of this skin cancer. Additionally, the implication of the endocannabinoid system in malignancy is actively investigated…

CONCLUSIONS:

This study suggests the interest of targeting the endocannabinoid system in the management of skin cancer and underlines the advantage of associating endocannabinoids with enzymatic hydrolysis inhibitors.

This may contribute to the improvement of long-term palliation or cure of melanoma.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364151/

Presence of functional cannabinoid receptors in human endocrine pancreas.

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“We examined the presence of functional cannabinoid receptors 1 and 2 (CB1, CB2) in isolated human islets, phenotyped the cells producing cannabinoid receptors and analysed the actions of selective cannabinoid receptor agonists on insulin, glucagon and somatostatin secretion in vitro. We also described the localisation on islet cells of: (1) the endocannabinoid-producing enzymes N-acyl-phosphatidyl ethanolamine-hydrolysing phospholipase D and diacylglycerol lipase; and (2) the endocannabinoid-degrading enzymes fatty acid amidohydrolase and monoacyl glycerol lipase.

RESULTS:

Human islets of Langerhans expressed CB1 and CB2 (also known as CNR1 and CNR2) mRNA and CB1 and CB2 proteins, and also the machinery involved in synthesis and degradation of 2-AG (the most abundant endocannabinoid, levels of which were modulated by glucose). Immunofluorescence revealed that CB1 was densely located in glucagon-secreting alpha cells and less so in insulin-secreting beta cells. CB2 was densely present in somatostatin-secreting delta cells, but absent in alpha and beta cells. In vitro experiments revealed that CB1 stimulation enhanced insulin and glucagon secretion, while CB2 agonism lowered glucose-dependent insulin secretion, showing these cannabinoid receptors to be functional.

CONCLUSIONS/INTERPRETATION:

Together, these results suggest a role for endogenous endocannabinoid signalling in regulation of endocrine secretion in the human pancreas.”

http://www.ncbi.nlm.nih.gov/pubmed/18092149

Role of endocannabinoid system in the ventral hippocampus of rats in the modulation of anxiety-like behaviours.

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“The effects of unilateral intra-ventral hippocampus injection of URB597, a fatty acid amid hydrolase inhibitor, and AM251, a selective CB(1) receptor antagonist, on anxiety-related behaviours using elevated plus-maze test of anxiety were evaluated in the present study. Possible involvement of GABAergic system in those effects of URB597 was also evaluated. Injection of URB597 at the doses of 0.01, 0.1 and 1 microg/rat showed significant anxiogenic-like effects at 0.1 and 1 microg/rat. However, intra-ventral hippocampus injection of AM251 at the doses of 0.001, 0.01 and 0.1 microg/rat did not produce any significant effect in the elevated plus-maze. The ineffective doses of selective GABA(A) receptor antagonist, bicuculline (2 microg/rat) and selective GABA(B) receptor antagonist, phaclofen (1 microg/rat) on anxiety-related behaviours were also injected with URB597 (0.1 microg/rat). The present data showed that neither bicuculline nor phaclofen affected the anxiogenic-like effects of URB597. The results showed that injection of URB597 into the ventral hippocampus may be anxiogenic and GABAergic system may not be involved in its anxiogenic-like effects.”

http://www.ncbi.nlm.nih.gov/pubmed/19614892

An Endocannabinoid Signaling System Modulates Anxiety-like Behavior in Male Syrian Hamsters

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“An endocannabinoid signaling system has not been identified in hamsters.

We examined the existence of an endocannabinioid signaling system in Syrian hamsters using neuroanatomical, biochemical and behavioral pharmacological approaches.

The distribution of cannabinoid receptors was mapped and membrane fatty-acid amide hydrolase (FAAH) activity and levels of fatty-acid amides were measured in hamster brain. The impact of cannabinoid CB1 receptor blockade and inhibition of FAAH was evaluated in the elevated plus maze, rota-rod test and models of unconditioned and conditioned social defeat.

Results

A characteristic heterogeneous distribution of cannabinoid receptors was detected in hamster brain..

Endocannabinoids engage functional CB1 receptors in hamster brain to suppress anxiety-like behavior and undergo enzymatic hydrolysis catalyzed by FAAH. Our results further suggest that neither unconditioned nor conditioned social defeat in the Syrian hamster is dependent upon cannabinoid CB1 receptor activation.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694060/

Anxiolytic Effects in Mice of a Dual Blocker of Fatty Acid Amide Hydrolase and Transient Receptor Potential Vanilloid Type-1 Channels

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“The endocannabinoid-inactivating enzyme, fatty acid amide hydrolase (FAAH), and the transient receptor potential vanilloid type-1 (TRPV1) channel are new targets for the development of anxiolytic drugs…

 Simultaneous ‘indirect’ activation of CB1 receptors following FAAH inhibition, and antagonism at TRPV1 receptors might represent a new therapeutic strategy against anxiety.”

http://www.nature.com/npp/journal/v34/n3/full/npp200898a.html