Neuroscience Letters 544 (2013) 1–4 Contents lists available at SciVerse ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Plenary article Dynamics of oxidative stress and urinary excretion of melatonin and its metabolites during acute ischemic stroke Thomas Ritzenthaler a , Isabelle Lhommeau b , Samuel Douillard b , Tea Hee Cho a , Jocelyne Brun c , Thierry Patrice b , Norbert Nighoghossian a,d , Bruno Claustrat c,e,* a Cerebrovascular Unit, Neurology Department, Pierre Wertheimer Hospital, 59 Boulevard Pinel, 69677 Bron, France b Laser Department, Laënnec Hospital, 44093 Nantes, France c Hormone Laboratory, Hospices Civils de Lyon, 59 Boulevard Pinel, 69677 Bron, France d UMR-CNRS 5220, INSERM U1044, Université de Lyon, France e INSERM, U846, Department of Chronobiologie, 18 Avenue du Doyen Lépine, 69500 Bron, France article info Keywords: Melatonin Oxidative stress Stroke, AFMK Antioxidant 6-Sulfatoxymelatonin abstract Oxidative stress is a leading cause of neuronal damage in ischemic stroke. Melatonin may play a role in the antioxidant response. Melatonin and its metabolites may be involved in the modulation of oxidative stress in human acute stroke. No data are available in humans to establish this relationship. In this context, on the first and the fifth days post-stroke, we assessed serum total antioxidant capacity (TAC) and urine levels of melatonin, 6-sulfatoxymelatonin (aMT6S), and N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), the last compound being produced in the brain after reaction of melatonin with reactive oxygen species. Compared to controls’ values, TAC and levels of melatonin and aMT6S were reduced, without difference between the first and the fifth days post-stroke, whereas AFMK levels remained in the normal range at both time points. Melatonin catabolism might be speeded up in acute ischemic stroke in order to increase the antioxidant response. © 2013 Published by Elsevier Ireland Ltd. 1. Introduction Oxidative stress is an imbalance between free reactive oxygen species (ROS) and their neutralization by antioxidant defense sys- tems. The ischemic cascade in stroke involves several mechanisms (excitotoxicity, inflammation, and mitochondrial dysfunction) and increased oxidative stress. In addition, defense against oxida- tive radicals is impaired [2]. Melatonin, an indolamine hormone mainly secreted by the pineal gland, can directly and indi- rectly detoxify free radicals [24] and contributes to the serum total antioxidant capacity (TAC) in humans [4]. Especially, a low affinity cytosolic binding site for the radiolabelled 2-[125I]- iodomelatonin designated as MT3 was identified as the same protein as human oxidoreductase 2 (QR2 protein) [6]. QR2 is also known as N-ribosyldihydronicotinamide: quinone oxidoreductase 2 (EC1.10.99.2) and is a detoxifying and antioxidant enzyme. Further, this hormone shows protective effects against ischemic damage in animals [19]. Melatonin treatment improved the sur- vival rate and neural functioning of the mice by reduction of stroke-induced free radical production [9]. Nocturnal urine levels of * Corresponding author at: Hormone Laboratory, Hospices Civils de Lyon, 59 Boulevard Pinel, 69677 Bron, France. E-mail address: bruno.claustrat@chu-lyon.fr (B. Claustrat). melatonin and of 6-sulfatoxymelatonin (aMT6S), the main hepatic metabolite of melatonin, are both indexes of the hormone secre- tion [5,22]. N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) is generated from melatonin via several pathways including enzy- matic, pseudo-enzymatic and interaction with a variety of ROS [26]. It displays an in vitro antioxidant capacity and is the last melatonin- related compound taking part in the process by which melatonin and its metabolites successively scavenge ROS, referred as the free radical scavenging cascade [27]. In order to counteract ROS over- generation, melatonin catabolism might be increased after stroke injury and could lead to increased production of AFMK. In a previ- ous study, we reported decreased melatonin and aMT6S excretion during the acute stage of ischemic stroke [25]. In this paper, we assessed kinetics of serum TAC and urine AFMK, melatonin and aMT6S levels in acute stroke. 2. Materials and methods 2.1. Patients and controls Consecutive patients with a first hemispheric ischemic stroke were prospectively included. Exclusion criteria were a past medi- cal history of stroke, renal or hepatic failure, or acute hemorrhagic stroke. The neurological status of the patients was evaluated using the National Institute of Health Stroke Scale (NIHSS) at baseline 0304-3940/$ – see front matter © 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.neulet.2013.02.073