Inhibition of neuronal nitric oxide synthase activity by N 1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin

Josefa León, Germaine Escames, María I. Rodríguez, Luis C. López, Víctor Tapias, Antonio Entrena, Encarnación Camacho, María D. Carrión, Miguel A. Gallo, Antonio Espinosa, Dun-xian Tan, Russel J. Reiter, Darío Acuña-Castroviejo

Research output: Contribution to journalArticlepeer-review

145 Scopus citations

Abstract

We assessed the effects of melatonin, N1-acetyl-N 2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5- methoxykynuramine (AMK) on neuronal nitric oxide synthase (nNOS) activity in vitro and in rat striatum in vivo. Melatonin and AMK (10-11-10 -3 M), but not AFMK, inhibited nNOS activity in vitro in a dose-response manner. The IC50 value for AMK (70 μm) was significantly lower than for melatonin (>1 mm). A 20% nNOS inhibition was reached with either 10-9 M melatonin or 10-11 M AMK. AMK inhibits nNOS by a non-competitive mechanism through its binding to Ca 2+-calmodulin (CaCaM). The inhibition of nNOS elicited by melatonin, but not by AMK, was blocked with 0.05 mM norharmane, an indoleamine-2,3- dioxygenase inhibitor. In vivo, the potency of AMK to inhibit nNOS activity was higher than that of melatonin, as a 25% reduction in rat striatal nNOS activity was found after the administration of either 10 mg/kg of AMK or 20 mg/kg of melatonin. Also, in vivo, the administration of norharmane blocked the inhibition of nNOS produced by melatonin administration, but not the inhibition produced by AMK. These data reveal that AMK rather than melatonin is the active metabolite against nNOS, which may be inhibited by physiological levels of AMK in the rat striatum.

Original languageEnglish (US)
Pages (from-to)2023-2033
Number of pages11
JournalJournal of neurochemistry
Volume98
Issue number6
DOIs
StatePublished - Sep 2006

Keywords

  • 3-dioxygenase
  • Indoleamine-2
  • Melatonin
  • N-acetyl-5- methoxykynuramine
  • Neuronal nitric oxide synthase
  • Norharmane
  • Rat striatum

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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