期刊
JOURNAL OF NEUROCHEMISTRY
卷 98, 期 6, 页码 2023-2033出版社
WILEY
DOI: 10.1111/j.1471-4159.2006.04029.x
关键词
indoleamine-2; 3-dioxygenase; melatonin; N-1-acetyl-5-methoxykynuramine; neuronal nitric oxide synthase; norharmane; rat striatum
We assessed the effects of melatonin, N-1-acetyl-N (2)-formyl-5-methoxykynuramine (AFMK) and N-1-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 mu M) 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 Ca2+-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.
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