Plasma 6-Hydroxymelatonin, 6-Sulfatoxymelatonin and Melatonin Kinetics after Melatonin Administration to Rats

Raynaud, FI; Mauviard, F.; Geoffriau, Martine; Bruno, Claudio; Pévet, Paul

doi:10.1159/000109516

Cited by 31 publications

(18 citation statements)

References 10 publications

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“…27 In brief, the analytical eluent consisted of 11.5% acetonitrile in a phosphate-citrate buffer (pH 7.4) and was delivered by a flow rate of 0.6 mL/min. Separation of the analytes were performed on a Hypersil ODS column (125 3 3 mm) with a particle size of 3 mm (MZ Analyventechnik, Mainz, Germany).…”

Section: Microsomal Incubations Extraction Procedure and High-perfomentioning

confidence: 99%

Differential Effects of Fluvoxamine and Other Antidepressants on the Biotransformation of Melatonin

Härtter¹,

Wang²,

Weigmann³

et al. 2001

Journal of Clinical Psychopharmacology

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Melatonin, the predominant product of the pineal gland, is involved in the maintenance of diurnal rhythms. Nocturnal blood concentrations of melatonin have been shown to be enhanced by fluvoxamine, but not by other serotonin reuptake inhibitors. Because fluvoxamine is an inhibitor of several cytochrome P450 (CYP) enzymes, the authors studied the biotransformation of melatonin and the effects of fluvoxamine on the metabolism of melatonin in vitro using human liver microsomes and recombinant human CYP isoenzymes. Melatonin was found to be almost exclusively metabolized by CYP1A2 to 6-hydroxymelatonin and N-acetylserotonin with a minimal contribution of CYP2C19. Both reactions were potently inhibited by fluvoxamine, with a Ki of 0.02 microM for the formation of 6-hydroxymelatonin and 0.05 microM for the formation of N-acetylserotonin. Other than fluvoxamine, fluoxetine, paroxetine, citalopram, imipramine, and desipramine were also tested at 2 and 20 microM. Among the other antidepressants, only paroxetine was able to affect the metabolism of melatonin at supratherapeutic concentrations of 20 microM, which did not reach by far the magnitude of the inhibitory potency of fluvoxamine. The authors concluded that fluvoxamine is a potent inhibitor of melatonin degradation. Because this inhibitory action is also found in vivo, fluvoxamine might be used as an enhancer of melatonin, which might offer new therapeutic possibilities of fluvoxamine.

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Section: Microsomal Incubations Extraction Procedure and High-perfomentioning

confidence: 99%

Differential Effects of Fluvoxamine and Other Antidepressants on the Biotransformation of Melatonin

Härtter¹,

Wang²,

Weigmann³

et al. 2001

Journal of Clinical Psychopharmacology

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“…Previous studies have shown that the half-life of MEL in the blood circulation is 20 min and that it is rapidly converted to 6-hydroxymelatonin (6-OH MEL) in the liver (32). This major metabolite has 50 times less binding affinity for plasma membranes than MEL, but it possesses a free radical-scavenging indole ring and therefore could maintain antioxidant activity.…”

mentioning

confidence: 99%

Melatonin as an effective protector against doxorubicin-induced cardiotoxicity

Liu¹,

Chen

Chua

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

136

103

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The present study was designed to explore the protective effects of melatonin and its analogs, 6-hydroxymelatonin and 8-methoxy-2-propionamidotetralin, on the survival of doxorubicin-treated mice and on doxorubicin-induced cardiac dysfunction, ultrastructural alterations, and apoptosis in mouse hearts. Whereas 60% of the mice treated with doxorubicin (25 mg/kg ip) died in 5 days, almost all the doxorubicin-treated mice survived when melatonin or 6-hydroxymelatonin (10 mg/l) was administered in their drinking water. Perfusion of mouse hearts with 5 μM doxorubicin for 60 min led to a 50% suppression of heart rate × left ventricular developed pressure and a 50% reduction of coronary flow. Exposure of hearts to 1 μM melatonin or 6-hydroxymelatonin reversed doxorubicin-induced cardiac dysfunction. 8-Methoxy-2-propionamidotetralin had no protective effects on animal survival and on in vitro cardiac function. Infusion of melatonin or 6-hydroxymelatonin (2.5 μg/h) significantly attenuated doxorubicin-induced cardiac dysfunction, ultrastructural alterations, and apoptosis in mouse hearts. Neither melatonin nor 6-hydroxymelatonin compromised the antitumor activity of doxorubicin in cultured PC-3 cells. These results suggest that melatonin protect against doxorubicin-induced cardiotoxicity without interfering with its antitumor effect.

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“…It is possible that epileptic discharges might have appeared in all rats examined in this study if EEG recordings had been continued for a longer period. Since plasma melatonin level decreases rapidly, with a half-life of 22.5 min after injection (28), it is possible that chronic administration of melatonin may prevent the development of epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Melatonin Inhibits Iron‐Induced Epileptic Discharges in Rats by Suppressing Peroxidation

1998

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Summary:Purpose: Intracortical injection of iron ion induces recurrent seizures and epileptic discharges in the electrocorticogram. This observation may be used as a model of posttraumatic epilepsy. The involvement of iron-mediated oxygen free radical species and neuronal lipid peroxidation in ironinduced seizure has been suggested. Melatonin exerts free radical scavenging properties. In this study, we examined the protective effect of melatonin against iron-induced seizures.Methods: We examined the protective effect of melatonin against in vitro iron-induced oxidative damage in homogenates from rat cerebral cortex, by measuring the concentration of thiobarbituric acid reactive substances (TBARS), as an index of oxidative damage. We also examined the effect of melatonin on the appearance of epileptic discharges in the EEG following injection of FeC1, into the sensorimotor cortex in anesthetized rats, and by measuring the concentration of TBARS in the brain tissue.Results: FeCI, increased the concentration of TBARS in brain homogenates in a concentration-dependent manner, and melatonin reduced FeC1,-induced rise in TBARS in a doseresponse fashion. Pretreatment with melatonin suppressed or delayed the development of FeC1,-induced epileptic discharges and decreased the concentration of TBARS in brain tissues.Conclusions: Our results suggest that iron ion generates oxygen free radical species that induce neuronal macromolecular peroxidation and seizure, and that melatonin inhibits ironinduced seizures by scavenging free radicals. Key Words: Melatonin-Iron-induced seizures-Perioxidation-Thiobarbituric acid-Reactive substances-TBARS-Free radical.Neurotrauma with extravasation of red blood cells followed by hemolysis and deposition of iron compounds such as hemosiderin within the brain tissue (1) is associated with the development of post-traumatic epilepsy (2). Similarly, intracortical injection of iron salts or heme compounds into the rodent brain induces recurrent seizures and epileptic discharges in the EEGs (3-5). These observations strongly suggest that trauma or hemorrhagic cortical infarction associated with extravasation of blood and decompartmentalization of iron within the brain may induce epileptic discharge (3, although the specific mechanisms of the epileptogenic effect of iron salts remain unknown. It has been proposed that active oxygen free radicals generated by iron-mediated reactions in the brain (6) peroxidize lipids in neural membranes, resulting in cell death and the formation of an epileptic focus (7). In support of this hypothesis, previ-

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Plasma 6-Hydroxymelatonin, 6-Sulfatoxymelatonin and Melatonin Kinetics after Melatonin Administration to Rats

Cited by 31 publications

References 10 publications

Differential Effects of Fluvoxamine and Other Antidepressants on the Biotransformation of Melatonin

Differential Effects of Fluvoxamine and Other Antidepressants on the Biotransformation of Melatonin

Melatonin as an effective protector against doxorubicin-induced cardiotoxicity

Melatonin Inhibits Iron‐Induced Epileptic Discharges in Rats by Suppressing Peroxidation

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