title: Fatty acid amidohydrolase in human neocortex-activity in epileptic and non-epileptic brain tissue and inhibition by putative endocannabinoids.
abstract: Increased levels of the endocannabinoid anandamide (AEA) have been observed in connection with neuronal disorders like epilepsy. In order to investigate whether an impaired enzymatic AEA hydrolysis contributes to this phenomenon, the present study determined the activity of fatty acid amidohydrolase (FAAH) in epileptic and non-epileptic human neocortical brain tissue. Additionally, we investigated whether other putative endocannabinoids (2-arachidonylglycerol (2-AG), noladin ether, virodhamine) may also interact with FAAH. AEA hydrolysis was measured by the formation of the product [(3)H]-ethanolamine after separation from the substrate using activated charcoal. FAAH activity was found to be similar in epileptic and non-epileptic human neocortex (0.29 and 0.37 nmol ethanolamine/mg protein/min, respectively). FAAH activity was about 55% higher in rat neocortex. While in human, neocortex noladin ether did not influence AEA hydrolysis, FAAH activity was concentration-dependently inhibited by AEA, 2-AG and virodhamine (IC(50) values 3.3, 3.5 and 13.8 microM, respectively). Our results suggest that, in the course of epilepsy, increased AEA levels are likely due to enhanced formation and not due to decreased hydrolysis. To further increase endocannabinoid activity, the application of FAAH inhibitors might be therapeutically useful in the treatment of neuronal hyperexcitability. Whereas noladin ether did not interact with AEA hydrolysis, this compound, 2-AG and virodhamine may share common enzymatic inactivation mechanisms in human neocortex.
authors.affiliation: Section of Clinical Neuropharmacology, Neurozentrum, Breisacher Strasse 64, 79106 Freiburg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Steffens
authors.forename: Andreas
authors.initials: A
authors.lastname: Schulze-Bonhage
authors.forename: Rainer
authors.initials: R
authors.lastname: Surges
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Feuerstein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D003164:Competitive Bidding / Q000379:methods; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004827:Epilepsy / Q000201:enzymology*; D019856:Ethanolamine / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D019579:Neocortex / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D012044:Regression Analysis; D014316:Tritium / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D019856:Ethanolamine; D014316:Tritium; D000099252:Fatty Acid Amide Hydrolases