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Cited by 121Cannabis and Cannabinoid ResearchNF-κB Signaling PathwaysNatural Compounds in Disease Treatment

Anandamide Inhibits Nuclear Factor-κB Activation through a Cannabinoid Receptor-Independent Pathway

Sancho, Rocío, Calzado, Marco A, Di Marzo, Vincenzo, Appendino, Giovanni, Muñoz, Eduardo·2003·Molecular Pharmacology
DOI 10.1124/mol.63.2.429
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Abstract

Anandamide (arachidonoylethanolamine, AEA), an endogenous agonist for both the cannabinoid CB(1) receptor and the vanilloid VR1 receptor, elicits neurobehavioral, anti-inflammatory, immunomodulatory, and proapoptotic effects. Because of the central role of nuclear factor-kappaB (NF-kappaB) in the inflammatory process and the immune response, we postulated that AEA might owe some of its effects to the suppression of NF-kappaB. This study shows that AEA inhibits tumor necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation by direct inhibition of the IkappaB kinase (IKK)beta and, to a lesser extent, the IKKalpha subunits of kappaB inhibitor (IkappaB) kinase complex, and that IKKs inhibition by AEA correlates with inhibition of IkappaBalpha degradation, NF-kappaB binding to DNA, and NF-kappaB-dependent transcription in TNFalpha-stimulated cells. AEA also prevents NF-kappaB-dependent reporter gene expression induced by mitogen-activated protein kinase kinase kinase and NF-kappaB-inducing kinase. The NF-kappaB inhibitory activity of AEA was independent of CB(1) and CB(2) activation in TNFalpha-stimulated 5.1 and A549 cell lines, which do not express vanilloid receptor 1, and was not mediated by hydrolytic products formed through the activity of the enzyme fatty acid amide hydrolase. Chemical modification markedly affected AEA inhibitory activity on NF-kappaB, suggesting rather narrow structure-activity relationships and the specific interaction with a molecular target. Substitution of the alkyl moiety with less saturated fatty acids generally reduced or abolished activity. However, replacement of the ethanolamine "head" with a vanillyl group led to potent inhibition of TNFalpha-induced NF-kappaB-dependent transcription. These findings provide new mechanistic insights into the anti-inflammatory and proapoptotic activities of AEA, and should foster the synthesis of improved analogs amenable to pharmaceutical development as anti-inflammatory agents.

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Authors
Sancho, R., Calzado, M. A., Di Marzo, V., Appendino, G., & Muñoz, E.
ORCID
Venue
Molecular Pharmacology
Publisher
Elsevier BV
Published
2003-02
Volume
63
Issue
2
Pages
429-438
ISSN
0026-895X (ISSN-L)
DOI
10.1124/mol.63.2.429
OpenAlex
W2110509314
Cited by
120
References
58
Citations by year
2026: 3 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 7 · 2019: 5 · 2018: 2 · 2017: 6 · 2016: 4 · 2015: 7 · 2014: 1 · 2013: 2 · 2012: 6
FWCI
6.64
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Molecular Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
Keywords
anandamide, nuclear factor-kappaB, IκB kinase β, IκBα degradation, TNF-α, anti-inflammatory activity, pro-apoptotic activity, structure-activity relationship, fatty acid amide hydrolase, vanilloid receptor 1, NIK, MAP3K, endocannabinoids
MeSH terms
NF-KappaB Inhibitor alpha, NF-kappaB-Inducing Kinase, Fatty Acid Amide Hydrolases, Amidohydrolases, Arachidonic Acids, Calcium Channel Blockers, Cell Line, Enzyme Activation, Humans, Receptors, Drug, Transcription, Genetic, Transfection, NF-kappa B, Protein Serine-Threonine Kinases, I-kappa B Proteins, Receptors, Cannabinoid, MAP Kinase Kinase Kinase 1, I-kappa B Kinase, Polyunsaturated Alkamides, Endocannabinoids

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