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ABSTRACT: Melatonin prevents mitochondrial failure in models of sepsis through its ability to inhibit the expression and activity of both cytosolic (iNOS) and mitochondrial (i-mtNOS) inducible nitric oxide synthases. Because Parkinson's disease (PD), like sepsis, is associated with iNOS induction, we assessed the existence of changes in iNOS/i-mtNOS and their relation with mitochondrial dysfunction in the MPTP model of PD, which also displays increased iNOS expression. We also evaluated the role of melatonin (aMT) and its brain metabolite, N(1)-acetyl-5-methoxykynuramine (AMK), in preventing i-mtNOS induction and mitochondrial failure in this model of PD. Mitochondria from substantia nigra (SN) and, to a lesser extent, from striatum (ST) showed a significant increase in i-mtNOS activity, nitrite levels, oxidative stress, and complex I inhibition after MPTP treatment. MPTP-induced i-mtNOS was probably related to mitochondrial failure, because its prevention by aMT and AMK reduced oxidative/nitrosative stress and restored complex I activity. These findings represent the first experimental evidence of a potential role for i-mtNOS in the mitochondrial failure of PD and support a novel mechanism in the neuroprotective effects of aMT and AMK.
Journal of Neuroscience Research 06/2009; 87(13):3002-10. · 2.74 Impact Factor
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ABSTRACT: We have previously described a series of 3-phenyl-4,5-dihydro-1H-pyrazole derivatives as moderately potent nNOS inhibitors. As a follow up of these studies, several new 5-phenyl-1H-pyrrole-2-carboxamide derivatives have been synthesized, and their biological evaluation as in vitro inhibitors of both neural and inducible Nitric Oxide Synthase (nNOS and iNOS) is described. Some of these compounds show good iNOS/nNOS selectivity and the more potent compounds 5-(2-aminophenyl)-1H-pyrrole-2-carboxilic acid methylamide (QFF205) and cyclopentylamide (QFF212) have been tested as regulators of the in vivo nNOS and iNOS activity. Both compounds prevented the increment of the inducible NOS activity in both cytosol (iNOS) and mitochondria (i-mtNOS) observed in the MPTP model of Parkinson's disease.
European journal of medicinal chemistry 01/2009; 44(6):2655-66. · 3.27 Impact Factor
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ABSTRACT: We have previously described a series of 4,5-dihydro-1H-pyrazole as moderately potent nNOS inhibitors. As a follow up of these studies, we report here the preparation and the preliminary evaluation of a series of 1-alkyl-3-benzoyl-4,5-dihydro-1H-pyrazole and 1-alkyl-3-benzoyl-1H-pyrazole as potential inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS). None of the reported compounds exhibited significant iNOS or nNOS inhibition, although the 1-benzyl-3-(2-amino-5-chlorobenzoyl)-1H-pyrazole-5-carboxylic acid ethyl ester derivative (10l), which shows an inhibition of 50% versus iNOS at a 1mM final concentration and no activity against nNOS, is potentially amenable of further optimization. The reasons for the inactivity of the reported series are discussed on the basis of docking studies.
European Journal of Medicinal Chemistry 02/2008; 43(11):2579-91. · 3.35 Impact Factor
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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
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ABSTRACT: 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 IC(50) value for AMK (70 microm) 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.
Journal of Neurochemistry 09/2006; 98(6):2023-33. · 4.06 Impact Factor
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ABSTRACT: Sepsis provokes an induction of inducible nitric oxide synthase (iNOS) and melatonin down-regulates its expression and activity. Looking for an inducible mtNOS isoform, we induced sepsis by cecal ligation and puncture in both normal and iNOS knockout mice and studied the changes in mtNOS activity. We also studied the effects of mtNOS induction in mitochondrial function, and the role of melatonin against induced mtNOS and mitochondrial dysfunction. The activity of mtNOS and nitrite levels significantly increased after sepsis in iNOS+/+ mice. These animals showed a significant inhibition of the respiratory chain activity and an increase in mitochondrial oxidative stress, reflected in the disulfide/glutathione ratio, glutathione redox cycling enzymes activity and lipid peroxidation levels. Interestingly, mtNOS activity remained unchanged in iNOS-/- septic mice, and mitochondria of these animals were unaffected by sepsis. Melatonin administration to iNOS+/+ mice counteracted mtNOS induction and respiratory chain failure, restoring the redox status. The results support the existence of an inducible mtNOS that is likely coded by the same gene as iNOS. The results also suggest that sepsis-induced mtNOS is responsible for the increase of mitochondrial impairment due to oxidative stress in sepsis, perhaps due to the high production of NO. Melatonin treatment prevents mitochondrial failure at the same extend as the lack of iNOS gene.
The International Journal of Biochemistry & Cell Biology 03/2006; 38(2):267-78. · 4.63 Impact Factor
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ABSTRACT: Mitochondrial nitric oxide synthase (mtNOS) produces nitric oxide (NO) to modulate mitochondrial respiration. Besides a constitutive mtNOS isoform it was recently suggested that mitochondria express an inducible isoform of the enzyme during sepsis. Thus, the mitochondrial respiratory inhibition and energy failure underlying skeletal muscle contractility failure observed in sepsis may reflect the high levels of NO produced by inducible mtNOS. The fact that mtNOS is induced during sepsis suggests its relation to inducible nitric oxide synthase (iNOS). Thus, we examined the changes in mtNOS activity and mitochondrial function in skeletal muscle of wild-type (iNOS(+/+)) and iNOS knockout (iNOS(-/-)) mice after sepsis. We also studied the effects of melatonin administration on mitochondrial damage in this experimental paradigm. After sepsis, iNOS(+/+) but no iNOS(-/-) mice showed an increase in mtNOS activity and NO production and a reduction in electron transport chain activity. These changes were accompanied by a pronounced oxidative stress reflected in changes in lipid peroxidation levels, oxidized glutathione/reduced glutathione ratio, and glutathione peroxidase and reductase activities. Melatonin treatment counteracted both the changes in mtNOS activity and rises in oxidative stress; the indole also restored mitochondrial respiratory chain in septic iNOS(+/+) mice. Mitochondria from iNOS(-/-) mice were unaffected by either sepsis or melatonin treatment. The data suggest that inducible mtNOS, which is coded by the same gene as that for iNOS, is responsible for mitochondrial dysfunction during sepsis. The results also suggest the use of melatonin for the protection against mtNOS-mediated mitochondrial failure.
Journal of Pineal Research 02/2006; 40(1):71-8. · 5.79 Impact Factor
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Antonio Entrena,
M Encarnación Camacho,
M Dora Carrión,
Luisa C López-Cara,
Guillermo Velasco,
Josefa León,
Germaine Escames,
Darío Acuña-Castroviejo, Víctor Tapias,
Miguel A Gallo,
Antonio Vivó,
Antonio Espinosa
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ABSTRACT: To find new compounds with potential neuroprotective activity, we have designed, synthesized, and characterized a series of neural nitric oxide synthase (nNOS) inhibitors with a kynurenamine structure. Among them, N-[3-(2-amino-5-methoxyphenyl)-3-oxopropyl]acetamide is the main melatonin metabolite in the brain and shows the highest activity in the series, with an inhibition percentage of 65% at a 1 mM concentration. The structure-activity relationship of the new series partially reflects that of the previously reported 2-acylamido-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acids, endowed with a kynurenine-like structure. Structural comparisons between these new kinurenamine derivatives, kynurenines, and 1-acyl-3-(2-amino-5-methoxyphenyl)-4,5-dihydro-1H-pyrazole derivatives also reported confirm our previous model for the nNOS inhibition.
Journal of Medicinal Chemistry 01/2006; 48(26):8174-81. · 5.25 Impact Factor
