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Effect of Fatty Acid Amide Hydrolase (FAAH) Inhibitors Isolated from Nutmeg on Anxiety
Author(s) -
ElAlfy Abir T.,
Jeon Andrew,
An Hea Re,
Kendrek Jennifer,
Abourashed Ehab
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb581
Subject(s) - fatty acid amide hydrolase , monoacylglycerol lipase , endocannabinoid system , cannabinoid receptor , nutmeg , chemistry , cannabinoid , myristica fragrans , pharmacology , cannabinoid receptor type 2 , elevated plus maze , biochemistry , anxiety , receptor , biology , psychology , medicine , agonist , traditional medicine , food science , psychiatry
The endocannabinoid system (ECS) is a complex neuromodulatory network involved in the regulation of numerous physiological functions. These effects have been substantiated by the use of known exogenous cannabinoid, Δ 9 ‐THC, the active component of marijuana. Thus, the ECS has emerged as an appealing pharmacologic target in drug discovery. Anecdotal reports of Myristica fragrans , commonly known as nutmeg, being used as a substitute for marijuana, suggest that one or more of its components may interact with the ECS. Previous studies in our laboratory demonstrated that administration of nutmeg extracts produced behavioral tetrad effects similar to Δ 9 ‐THC. However, the mechanism of such action requires further exploration. Receptor binding assays revealed that nutmeg extracts did not have direct CB1 or CB2 receptor binding activity. Additional mechanistic studies showed that indirect interaction through the inhibition of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), key endocannabinoid degradation enzymes, was observed. The objective of the current study was to isolate the active components of nutmeg extract responsible for the FAAH inhibition activity and to evaluate them in an animal model of anxiety. Using bioassay guided fractionation and various chromatographic techniques, three compounds were isolated, spectroscopically characterized, and identified (MF 109‐5, MF30‐7, and MF117‐3). Concentration and time inhibition studies were conducted. The IC 50 values calculated for the three compounds were 4.57 ± 0.66, 7.50 ± 2.02, and 38.29 ± 6.18 mM, respectively. The compounds were further evaluated in the elevated plus maze animal model of anxiety in comparison to diazepam as the positive control. The three nutmeg compounds were tested at doses ranging from 5 to 120 mg/kg, i.p. injection. While diazepam demonstrated a significant dose‐response increase in open arm entry and permanence time, indicative of anxiolytic action, none of the isolated compounds had a significant effect. In conclusion, the study resulted in the identification of three nutmeg compounds that significantly inhibit FAAH enzyme and hence shed light on potential mechanism of cannabis‐like action of nutmeg. While none of the compounds showed anxiolytic activity in the elevated plus maze model, additional pharmacokinetic studies are needed to optimize the dosing regimen required for significant increase in endocannabinoids that might be needed for elaboration of the anxiolytic effect. Support or Funding Information Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under Award Number R24DA036410. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.