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AM404 and VDM 11 non-specifically inhibit C6 glioma cell proliferation at concentrations used to block the cellular accumulation of the endocannabinoid anandamide.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience.
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2003 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 77, no 4, 201-207 p.Article in journal (Refereed) Published
Abstract [en]

AM404 [ N-(4-hydroxyphenyl)arachidonylamide] and VDM 11 [(5 Z,8 Z,11 Z,14 Z)- N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide] are commonly used to prevent the cellular accumulation of the endocannabinoid anandamide, and thereby to potentiate its actions. However, it has been reported that AM404 can produce an influx of calcium into cells, which might be expected to have deleterious effects on cell proliferation. In the present study, AM404 and VDM 11 were found to reduce C6 glioma cell proliferation with IC(50) values of 4.9 and 2.7 microM, respectively. The inhibition of cell proliferation following a 96-h exposure was not accompanied by dramatic caspase activation, and was not prevented by either a combination of cannabinoid and vanilloid receptor antagonists, or by the antioxidant alpha-tocopherol, suggestive of a non-specific mode of action. Similar results were seen with palmitoylisopropylamide, although this compound only produced significant inhibition of cell proliferation at 30 microM concentrations. AM404 (1 microM), VDM 11 (1 microM) and palmitoylisopropylamide (3-30 microM), i.e. concentrations producing relatively modest effects on cell proliferation per se, reduced the vanilloid receptor-mediated antiproliferative effects of anandamide, as would be expected for compounds preventing the cellular accumulation of anandamide (and thereby access to its binding site on the vanilloid receptor). It is concluded that concentrations of AM404 and VDM 11 that are generally used to reduce the cellular accumulation of anandamide have deleterious effects upon cell proliferation, and that lower concentrations of these compounds may be more appropriate to use in vitro.

Place, publisher, year, edition, pages
2003. Vol. 77, no 4, 201-207 p.
Identifiers
URN: urn:nbn:se:umu:diva-4394DOI: 10.1007/s00204-002-0435-6PubMedID: 12698235OAI: oai:DiVA.org:umu-4394DiVA: diva2:143473
Available from: 2005-02-09 Created: 2005-02-09 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Pharmacology of Palmitoylethanolamide and Related Compounds
Open this publication in new window or tab >>Pharmacology of Palmitoylethanolamide and Related Compounds
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Anandamide (AEA) is an endogenous fatty acid which activates the same cannabinoid receptors as ∆9-tetrahydrocannabinol, the psychoactive substance in marijuana. In vivo, anandamide exerts a number of actions including effects upon pain and inflammation. However, AEA has a short duration of action since it is rapidly metabolised, primarily by the intracellular enzyme fatty acid amide hydrolase (FAAH).

The general aim of this thesis has been to identify and characterize compounds capable of preventing the metabolism of anandamide. The chemical approach was based on the endogenous anti-inflammatory compound palmitoylethanolamide (PEA), a compound related to anandamide with the ability to inhibit anandamide degradation by substrate competition, but without the ability to directly activate cannabinoid receptors.

A number of compounds were identified as inhibitors of rat brain FAAH in the initial in vitro studies, without having major affinity for the cannabinoid receptors. In particular, palmitoylisopropylamide (PIA) was found to reduce the metabolism of AEA in intact C6 glioma cells with potency similar to the prototypical AEA reuptake inhibitor AM404. This compound was in addition found to exert less effect upon C6 glioma cell proliferation than either AM404 or the closely related uptake inhibitor VDM11. To evaluate if PIA was effective in vivo, a model of mast cell dependent inflammation, oedema of the ear following local injection of compound 48/80, was set up using anaesthetised mice. Initially, a CB2 cannabinoid receptor selective agonist was used to probe the model and demonstrated to produce an anti-oedema effect. In contrast, the compound was inactive in vitro in skin slice preparations. PIA showed a similar pattern, although there was a large variation in responses which affected the significance of the result obtained, as did the vehicle used to dissolve the compound.

Taken together, the present data would suggest that PIA can inhibit the degradation of AEA without having deleterious effects upon cell proliferation or affinity for the cannabinoid receptors. Further experimentation is necessary to elucidate the usefulness of this compound in vivo.

Place, publisher, year, edition, pages
Umeå: Farmakologi och klinisk neurovetenskap, 2005. 82 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 942
Keyword
Pharmacology, anandamide, cannabinoid, FAAH, palmitoylethanolamide, palmitoylisopropylamide, inflammation, mast cells, Farmakologi
National Category
Pharmacology and Toxicology
Research subject
Medical Pharmacology
Identifiers
urn:nbn:se:umu:diva-445 (URN)91-7305-821-1 (ISBN)
Public defence
2005-03-04, E04, 6E, Norrlands universitetssjukhus, Umeå, 09:00 (English)
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Supervisors
Available from: 2005-02-09 Created: 2005-02-09 Last updated: 2009-11-17Bibliographically approved

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