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Acyl-based anandamide uptake inhibitors cause rapid toxicity to C6 glioma cells at pharmacologically relevant concentrations.

Abstract
Compounds blocking the uptake of the endogenous cannabinoid anandamide (AEA) have been used to explore the functions of the endogenous cannabinoid system in the CNS both in vivo and in vitro. In this study, the effects of four commonly used acyl-based uptake inhibitors [N-(4-hydroxyphenyl)arachidonylamide (AM404), N-(4-hydroxy-2-methylphenyl) arachidonoyl amide (VDM11), (5Z,8Z,11Z,14Z)-N-(3-furanylmethyl)-5,8,11,14-eicosatetraenamide (UCM707) and (9Z)-N-[1-((R)-4-hydroxybenzyl)-2-hydroxyethyl]-9-octadecen-amide (OMDM2)] and the related compound arvanil on C6 glioma cell viability were investigated. All five compounds reduced the ability of the cells to accumulate calcein, reduced the total nucleic acid content and increased the activity of lactate dehydrogenase recovered in the cell medium. AM404 (10 microm) and VDM11 (10 microm) acted rapidly, reducing cell viability after 3 h of exposure when cell densities of 5,000 per well were used. In contrast, UCM707 (30 microm), OMDM2 (10 microm) and the related compound arvanil (10 microm) produced a more slowly developing effect on cell viability, although robust effects were seen after 6-9 h of exposure. At higher cell densities, the toxicities of AM404 and UCM707 were reduced. Comparison of the compounds with arachidonic acid, arachidonic acid methyl ester, AEA, arachidonoyl glycine and oleic acid suggested that the toxicity of the arachidonoyl-based compounds was related primarily to the acyl side-chain rather than the head group. A variety of pre-treatments blocking possible metabolic pathways and receptor targets were tested, but the only consistent protective treatment against the effects of these compounds was the antioxidant N-acetyl-L-cysteine. It is concluded that AM404, VDM11, UCM707 and OMDM2 produce a rapid loss of C6 glioma cell viability over the same concentration range as is required for the inhibition of AEA uptake in vitro, albeit with a longer latency. Such effects should be kept in mind when acyl-derived compounds are used to probe the function of the endocannabinoid system in the CNS, particularly in chronic administration protocols.
AuthorsEva De Lago, Sofia B Gustafsson, Javier Fernández-Ruiz, Jonas Nilsson, Stig O P Jacobsson, Christopher J Fowler
JournalJournal of neurochemistry (J Neurochem) Vol. 99 Issue 2 Pg. 677-88 (Oct 2006) ISSN: 0022-3042 [Print] England
PMID16899063 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Arachidonic Acids
  • Benzyl Compounds
  • Cannabinoid Receptor Modulators
  • Cytotoxins
  • Endocannabinoids
  • Fluoresceins
  • Furans
  • N-(2-methyl-3-hydroxyphenyl)-5,8,11,14-eicosatetraenamide
  • N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide
  • N-(4-hydroxyphenyl)arachidonylamide
  • Nucleic Acids
  • OMDM-2 cpd
  • Polyunsaturated Alkamides
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • anandamide
  • L-Lactate Dehydrogenase
  • fluorexon
Topics
  • Acylation (drug effects)
  • Animals
  • Antineoplastic Agents (chemistry, toxicity)
  • Arachidonic Acids (antagonists & inhibitors, chemistry, metabolism, toxicity)
  • Benzyl Compounds (chemistry, toxicity)
  • Brain (drug effects, metabolism)
  • Brain Neoplasms (drug therapy, metabolism, physiopathology)
  • Cannabinoid Receptor Modulators (antagonists & inhibitors, metabolism)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects, physiology)
  • Cytotoxins (chemistry, toxicity)
  • Drug Screening Assays, Antitumor
  • Endocannabinoids
  • Fluoresceins (metabolism)
  • Furans (chemistry, toxicity)
  • Glioma (drug therapy, metabolism, physiopathology)
  • L-Lactate Dehydrogenase (metabolism)
  • Neurons (drug effects, metabolism)
  • Nucleic Acids (metabolism)
  • Polyunsaturated Alkamides (antagonists & inhibitors, chemistry, metabolism, toxicity)
  • Rats
  • TRPV Cation Channels (drug effects, metabolism)
  • Time Factors

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