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 journalArticle

125 Citations (Scopus)

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

Fingerprint

Nitric Oxide Synthase Type I
Melatonin
Metabolites
Brain
norharman
Rats
Indoleamine-Pyrrole 2,3,-Dioxygenase
N-acetyl-5-methoxy kynurenamine
Corpus Striatum
Calmodulin
Inhibitory Concentration 50

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

Cite this

León, J., Escames, G., Rodríguez, M. I., López, L. C., Tapias, V., Entrena, A., ... Acuña-Castroviejo, D. (2006). Inhibition of neuronal nitric oxide synthase activity by N 1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin. Journal of Neurochemistry, 98(6), 2023-2033. https://doi.org/10.1111/j.1471-4159.2006.04029.x

Inhibition of neuronal nitric oxide synthase activity by N 1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin. / León, Josefa; Escames, Germaine; Rodríguez, María I.; López, Luis C.; Tapias, Víctor; Entrena, Antonio; Camacho, Encarnación; Carrión, María D.; Gallo, Miguel A.; Espinosa, Antonio; Tan, Dun Xian; Reiter, Russel J; Acuña-Castroviejo, Darío.

In: Journal of Neurochemistry, Vol. 98, No. 6, 09.2006, p. 2023-2033.

Research output: Contribution to journalArticle

León, J, Escames, G, Rodríguez, MI, López, LC, Tapias, V, Entrena, A, Camacho, E, Carrión, MD, Gallo, MA, Espinosa, A, Tan, DX, Reiter, RJ & Acuña-Castroviejo, D 2006, 'Inhibition of neuronal nitric oxide synthase activity by N 1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin', Journal of Neurochemistry, vol. 98, no. 6, pp. 2023-2033. https://doi.org/10.1111/j.1471-4159.2006.04029.x
León, Josefa ; Escames, Germaine ; Rodríguez, María I. ; López, Luis C. ; Tapias, Víctor ; Entrena, Antonio ; Camacho, Encarnación ; Carrión, María D. ; Gallo, Miguel A. ; Espinosa, Antonio ; Tan, Dun Xian ; Reiter, Russel J ; Acuña-Castroviejo, Darío. / Inhibition of neuronal nitric oxide synthase activity by N 1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin. In: Journal of Neurochemistry. 2006 ; Vol. 98, No. 6. pp. 2023-2033.
@article{02dfc5ac1c7e48c3beeae8151e7082ce,
title = "Inhibition of neuronal nitric oxide synthase activity by N 1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin",
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.",
keywords = "3-dioxygenase, Indoleamine-2, Melatonin, N-acetyl-5- methoxykynuramine, Neuronal nitric oxide synthase, Norharmane, Rat striatum",
author = "Josefa Le{\'o}n and Germaine Escames and Rodr{\'i}guez, {Mar{\'i}a I.} and L{\'o}pez, {Luis C.} and V{\'i}ctor Tapias and Antonio Entrena and Encarnaci{\'o}n Camacho and Carri{\'o}n, {Mar{\'i}a D.} and Gallo, {Miguel A.} and Antonio Espinosa and Tan, {Dun Xian} and Reiter, {Russel J} and Dar{\'i}o Acu{\~n}a-Castroviejo",
year = "2006",
month = "9",
doi = "10.1111/j.1471-4159.2006.04029.x",
language = "English (US)",
volume = "98",
pages = "2023--2033",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - Inhibition of neuronal nitric oxide synthase activity by N 1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin

AU - León, Josefa

AU - Escames, Germaine

AU - Rodríguez, María I.

AU - López, Luis C.

AU - Tapias, Víctor

AU - Entrena, Antonio

AU - Camacho, Encarnación

AU - Carrión, María D.

AU - Gallo, Miguel A.

AU - Espinosa, Antonio

AU - Tan, Dun Xian

AU - Reiter, Russel J

AU - Acuña-Castroviejo, Darío

PY - 2006/9

Y1 - 2006/9

N2 - 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.

AB - 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.

KW - 3-dioxygenase

KW - Indoleamine-2

KW - Melatonin

KW - N-acetyl-5- methoxykynuramine

KW - Neuronal nitric oxide synthase

KW - Norharmane

KW - Rat striatum

UR - http://www.scopus.com/inward/record.url?scp=33748042003&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33748042003&partnerID=8YFLogxK

U2 - 10.1111/j.1471-4159.2006.04029.x

DO - 10.1111/j.1471-4159.2006.04029.x

M3 - Article

VL - 98

SP - 2023

EP - 2033

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 6

ER -