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      Melatonin Counteracts at a Transcriptional Level the Inflammatory and Apoptotic Response Secondary to Ischemic Brain Injury Induced by Middle Cerebral Artery Blockade in Aging Rats

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          Abstract

          Aging increases oxidative stress and inflammation. Melatonin counteracts inflammation and apoptosis. This study investigated the possible protective effect of melatonin on the inflammatory and apoptotic response secondary to ischemia induced by blockade of the right middle cerebral artery (MCA) in aging male Wistar rats. Animals were subjected to MCA obstruction. After 24 h or 7 days of procedure, 14-month-old nontreated and treated rats with a daily dose of 10 mg/kg melatonin were sacrificed and right and left hippocampus and cortex were collected. Rats aged 2 and 6 months, respectively, were subjected to the same brain injury protocol, but they were not treated with melatonin. mRNA expression of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), Bcl-2-associated death promoter (BAD), Bcl-2-associated X protein (BAX), glial fibrillary acidic protein (GFAP), B-cell lymphoma 2 (Bcl-2), and sirtuin 1 was measured by reverse transcription–polymerase chain reaction. In nontreated animals, a significant time-dependent increase in IL-1β, TNF-α, BAD, and BAX was observed in the ischemic area of both hippocampus and cortex, and to a lesser extent in the contralateral hemisphere. Hippocampal GFAP was also significantly elevated, while Bcl-2 and sirtuin 1 decreased significantly in response to ischemia. Aging aggravated these changes. Melatonin administration was able to reverse significantly these alterations. In conclusion, melatonin may ameliorate the age-dependent inflammatory and apoptotic response secondary to ischemic cerebral injury.

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          Most cited references 38

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          Dose translation from animal to human studies revisited.

          As new drugs are developed, it is essential to appropriately translate the drug dosage from one animal species to another. A misunderstanding appears to exist regarding the appropriate method for allometric dose translations, especially when starting new animal or clinical studies. The need for education regarding appropriate translation is evident from the media response regarding some recent studies where authors have shown that resveratrol, a compound found in grapes and red wine, improves the health and life span of mice. Immediately after the online publication of these papers, the scientific community and popular press voiced concerns regarding the relevance of the dose of resveratrol used by the authors. The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight, as was reported. For the more appropriate conversion of drug doses from animal studies to human studies, we suggest using the body surface area (BSA) normalization method. BSA correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function. We advocate the use of BSA as a factor when converting a dose for translation from animals to humans, especially for phase I and phase II clinical trials.
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            Role of oxidants in ischemic brain damage.

             Paul K S Chan (1996)
            Oxygen free radicals or oxidants have been proposed to be involved in acute central nervous system injury that is produced by cerebral ischemia and reperfusion. Because of the transient nature of oxygen radicals and the technical difficulties inherent in accurately measuring their levels in the brain, experimental strategies have been focused on the use of pharmacological agents and antioxidants to seek a correlation between the exogenously supplied specific radical scavengers (ie, superoxide dismutase and catalase) and the subsequent protection of cerebral tissues from ischemic injury. However, this strategy entails problems (hemodynamic, pharmacokinetic, toxicity, blood-brain barrier permeability, etc) that may cloud the data interpretation. This mini-review will focus on the oxidant mechanisms in cerebral ischemic brain injury by using transgenic and knockout mice as an alternative approach. Transgenic and knockout mutants that either overexpress or are deficient in antioxidant enzyme/protein levels have been successfully produced. The availability of these genetically modified animals has made it possible to investigate the role of certain oxidants in ischemic brain cell damage in molecular fashion. It has been shown that an increased level of CuZn-superoxide dismutase and antiapoptotic protein Bcl-2 in the brains of transgenic mice protects neurons from ischemic/reperfusion injury, whereas a deficiency in CuZn-superoxide dismutase or mitochondrial Mn-superoxide dismutase exacerbates ischemic brain damage. Target disruption of neuronal nitric oxide synthase in mice also provides neuronal protection against permanent and transient focal cerebral ischemia. I conclude that molecular genetic approaches in modifying antioxidant levels in the brain offer a unique tool for understanding the role of oxidants in ischemic brain damage.
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              A review of the molecular aspects of melatonin's anti-inflammatory actions: recent insights and new perspectives.

              Melatonin is a highly evolutionary conserved endogenous molecule that is mainly produced by the pineal gland, but also by other nonendocrine organs, of most mammals including man. In the recent years, a variety of anti-inflammatory and antioxidant effects have been observed when melatonin is applied exogenously under both in vivo and in vitro conditions. A number of studies suggest that this indole may exert its anti-inflammatory effects through the regulation of different molecular pathways. It has been documented that melatonin inhibits the expression of the isoforms of inducible nitric oxide synthase and cyclooxygenase and limits the production of excessive amounts of nitric oxide, prostanoids, and leukotrienes, as well as other mediators of the inflammatory process such as cytokines, chemokines, and adhesion molecules. Melatonin's anti-inflammatory effects are related to the modulation of a number of transcription factors such as nuclear factor kappa B, hypoxia-inducible factor, nuclear factor erythroid 2-related factor 2, and others. Melatonin's effects on the DNA-binding capacity of transcription factors may be regulated through the inhibition of protein kinases involved in signal transduction, such as mitogen-activated protein kinases. This review summarizes recent research data focusing on the modulation of the expression of different inflammatory mediators by melatonin and the effects on cell signaling pathways responsible for the indole's anti-inflammatory activity. Although there are a numerous published reports that have analyzed melatonin's anti-inflammatory properties, further studies are necessary to elucidate its complex regulatory mechanisms in different cellular types and tissues. © 2012 John Wiley & Sons A/S.
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                Author and article information

                Journal
                Biores Open Access
                Biores Open Access
                biores
                BioResearch Open Access
                Mary Ann Liebert, Inc. (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                2164-7844
                2164-7860
                01 October 2015
                2015
                01 October 2015
                : 4
                : 1
                : 407-416
                Affiliations
                [ 1 ]Department of Physiology, School of Medicine, Complutense University of Madrid , Madrid, Spain.
                [ 2 ]Department of Biochemistry and Molecular Biology III, School of Medicine, Complutense University of Madrid , Madrid, Spain.
                [ 3 ]Instituto de Investigación Biomédica de Vigo (IBIV), Xerencia de Xestión Integrada de Vigo, SERGAS, Biomedical Research Unit, Hospital Rebullón (CHUVI) , Vigo, Spain.
                [ 4 ]Experimental Medicine and Surgery Unit, Hospital Clínico San Carlos , Madrid, Spain.
                Author notes
                [*]

                The first two authors contributed equally.

                [ ]Address correspondence to: Jesús A.F. Tresguerres, MD, PhD, Department of Physiology, School of Medicine, Complutense University of Madrid, Avda. Complutense, s/n, Madrid 28040, Spain, E-mail: guerres@ 123456ucm.es
                Article
                10.1089/biores.2015.0032
                10.1089/biores.2015.0032
                4642830
                © Sergio D. Paredes et al. 2015; Published by Mary Ann Liebert, Inc.

                This Open Access article is distributed under the terms of the Creative Commons License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

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                Figures: 7, Tables: 1, References: 40, Pages: 10
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