FAAH inhibition attenuates TLR3-mediated hyperthermia, nociceptive- and anxiety-like behaviour in female rats

Flannery, Lisa E.; Kerr, Daniel M.; Finn, David P.; Roche, M.

doi:10.1016/j.bbr.2018.06.030

Cited by 27 publications

(23 citation statements)

References 51 publications

(92 reference statements)

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“…Such anxiolytic effect was not confounded by effects on locomotor function, whereby compound 8 did not alter total locomotor activity in the open field activity chamber test. Similar effects have been reported with other FAAH inhibitors …”

Section: Discussionsupporting

confidence: 89%

Phenolic compounds from nutmeg (Myristica fragrans Houtt.) inhibit the endocannabinoid-modulating enzyme fatty acid amide hydrolase

El‐Alfy

Abourashed

Patel

et al. 2019

Journal of Pharmacy and Pharmacology

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ObjectivesThe study aimed to identify nutmeg compounds that indirectly interact with the endocannabinoid system through inhibition of the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) enzymes. Methods Thirteen compounds were screened for FAAH and MAGL inhibition. Compounds demonstrating significant FAAH inhibition were evaluated to determine the halfmaximal inhibitory concentration (IC 50 ). The most potent compound was investigated in the elevated plus maze (EPM) rodent anxiety model. Key findings Three compounds, licarin A (9), 5 0 -methoxylicarin A (8) and malabaricone C (6) were most active in inhibiting FAAH with IC 50 of 7.02 lM AE 2.02, 4.57 lM AE 0.66 and 38.29 lM AE 6.18, respectively. None of the purified compounds showed significant MAGL inhibition. Because of its relative high potency and selectivity, compound 8 was further evaluated in the EPM animal model of anxiety. The compound showed significant increase in number of open arm entries (P < 0.05) when administered at 120 mg/kg dose. No effect was observed on the locomotor activity.Conclusions Results collected introduce active nutmeg compounds as potential leads for further development. Of the three compounds, 8 possesses highest potency and FAAH selectivity as well as anxiolytic activity. Furthermore, in vivo testing in appropriate behavioural animal paradigms is warranted.FAAH inhibitors from nutmeg Abir T. El-Alfy et al.

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Section: Discussionsupporting

confidence: 89%

Phenolic compounds from nutmeg (Myristica fragrans Houtt.) inhibit the endocannabinoid-modulating enzyme fatty acid amide hydrolase

El‐Alfy

Abourashed

Patel

et al. 2019

Journal of Pharmacy and Pharmacology

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“…It has been shown that deletion of CB1 accelerates brain aging through tumor necrosis factor α (TNF-α) [166], while CB1 agonism decreases neuroinflammation [167]. There have also been studies on FAAH inhibition impact on decreasing neuroinflammation [168] and exitoxicity in rodent models [169]. Moreover, a GPR55 inverse agonist, KIT 17, in vitro inhibited PGE2 release in microglia (cells important for CNS immune functions), and thus may be further studied as a potential anti-neuroinflammatory agent [170].…”

Section: Neurodegenerationmentioning

confidence: 99%

“…FAAH inhibitors proved to be anti-inflammatory agents in vitro and in rodent models. In detail, they reduce PGE2 production, downregulate COX-2, reduce expression of pro-inflammatory cytokines, reduce inducible nitric oxide synthase (iNOS) activity, and alleviate TLR3 mediated fever [168,204,205]. The role of TRPV1 remains unclear.…”

Section: Inflammatory and Autoimmune Diseasesmentioning

confidence: 99%

A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

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The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.

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“…Research has demonstrated the involvement of the endocannabinoid system in the regulation of various physiological operations including pain, inflammation, gastrointestinal, metabolic and cardiovascular function, and has been recently proposed as a potential therapeutic target in psychiatry and for anxiety disorders 18. In particular, preclinical studies reported that inhibition of the fatty acid amide hydrolase and monoacylglycerol lipase leads to increased signalling in the endocannabinoid system and was associated with reductions in anxiety-like behaviours in rodents 19. However, other agents to regulate the endocannabinoid system have also been proposed 20.…”

Section: Novel Promising Pharmacological Pathwaysmentioning

confidence: 99%

Pharmacotherapy of anxiety disorders in the 21st century: A call for novel approaches

2019

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While limited advances have occurred in the past 30 years in the pharmacological management of anxiety and stressrelated disorders, novel molecular pathways both within and without the monoamine systems are currently under investigation and offer promising new avenues for more effective future treatments. Enhancing psychotherapy approaches with pharmacological compounds offers the potential to not only transform the standard of care of these conditions, but more broadly would introduce a paradigm shift in the way medications and their role in psychiatric care are conceptualised. Although further human trials and more translational research are sorely needed, continuing to pursue innovative mechanisms and treatments is hoped to yield substantial results in the coming decades and a departure from the reliance on chemical agents of the 20th century.

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FAAH inhibition attenuates TLR3-mediated hyperthermia, nociceptive- and anxiety-like behaviour in female rats

Cited by 27 publications

References 51 publications

Phenolic compounds from nutmeg (Myristica fragrans Houtt.) inhibit the endocannabinoid-modulating enzyme fatty acid amide hydrolase

Phenolic compounds from nutmeg (Myristica fragrans Houtt.) inhibit the endocannabinoid-modulating enzyme fatty acid amide hydrolase

A Guide to Targeting the Endocannabinoid System in Drug Design

Pharmacotherapy of anxiety disorders in the 21st century: A call for novel approaches

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