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
C2 - 16945113
AN - SCOPUS:33748042003
SN - 0022-3042
VL - 98
SP - 2023
EP - 2033
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 6
ER -