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      The CORM ALF-186 Mediates Anti-Apoptotic Signaling via an Activation of the p38 MAPK after Ischemia and Reperfusion Injury in Retinal Ganglion Cells

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          Abstract

          Purpose

          Ischemia and reperfusion injury may induce apoptosis and lead to sustained tissue damage and loss of function, especially in neuronal organs. While carbon monoxide is known to exert protective effects after various harmful events, the mechanism of carbon monoxide releasing molecules in neuronal tissue has not been investigated yet. We hypothesize that the carbon monoxide releasing molecule (CORM) ALF-186, administered after neuronal ischemia-reperfusion injury (IRI), counteracts retinal apoptosis and its involved signaling pathways and consecutively reduces neuronal tissue damage.

          Methods

          IRI was performed in rat´s retinae for 1 hour. The water-soluble CORM ALF-186 (10 mg/kg) was administered intravenously via a tail vein after reperfusion. After 24 and 48 hours, retinal tissue was harvested to analyze mRNA and protein expression of Bcl-2, Bax, Caspase-3, ERK1/2, p38 and JNK. Densities of fluorogold pre-labeled retinal ganglion cells (RGC) were analyzed 7 days after IRI. Immunohistochemistry was performed on retinal cross sections.

          Results

          ALF-186 significantly reduced IRI mediated loss of RGC. ALF-186 treatment differentially affected mitogen-activated protein kinases (MAPK) phosphorylation: ALF-186 activated p38 and suppressed ERK1/2 phosphorylation, while JNK remained unchanged. Furthermore, ALF-186 treatment affected mitochondrial apoptosis, decreasing pro-apoptotic Bax and Caspase-3-cleavage, but increasing anti-apoptotic Bcl-2. Inhibition of p38-MAPK using SB203580 reduced ALF-186 mediated anti-apoptotic effects.

          Conclusion

          In this study, ALF-186 mediated substantial neuroprotection, affecting intracellular apoptotic signaling, mainly via MAPK p38. CORMs may thus represent a promising therapeutic alternative treating neuronal IRI.

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          Most cited references38

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          The therapeutic potential of carbon monoxide.

          Carbon monoxide (CO) is increasingly being accepted as a cytoprotective and homeostatic molecule with important signalling capabilities in physiological and pathophysiological situations. The endogenous production of CO occurs through the activity of constitutive (haem oxygenase 2) and inducible (haem oxygenase 1) haem oxygenases, enzymes that are responsible for the catabolism of haem. Through the generation of its products, which in addition to CO includes the bile pigments biliverdin, bilirubin and ferrous iron, the haem oxygenase 1 system also has an obligatory role in the regulation of the stress response and in cell adaptation to injury. This Review provides an overview of the physiology of CO, summarizes the effects of CO gas and CO-releasing molecules in preclinical animal models of cardiovascular disease, inflammatory disorders and organ transplantation, and discusses the development and therapeutic options for the exploitation of this simple gaseous molecule.
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            Molecular targets in cerebral ischemia for developing novel therapeutics.

            Cerebral ischemia (stroke) triggers a complex series of biochemical and molecular mechanisms that impairs the neurologic functions through breakdown of cellular integrity mediated by excitotoxic glutamatergic signalling, ionic imbalance, free-radical reactions, etc. These intricate processes lead to activation of signalling mechanisms involving calcium/calmodulin-dependent kinases (CaMKs) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). The distribution of these transducers bring them in contact with appropriate molecular targets leading to altered gene expression, e.g. ERK and JNK mediated early gene induction, responsible for activation of cell survival/damaging mechanisms. Moreover, inflammatory reactions initiated at the neurovascular interface and alterations in the dynamic communication between the endothelial cells, astrocytes and neurons are thought to substantially contribute to the pathogenesis of the disease. The damaging mechanisms may proceed through rapid nonspecific cell lysis (necrosis) or by active form of cell demise (apoptosis or necroptosis), depending upon the severity and duration of the ischemic insult. A systematic understanding of these molecular mechanisms with prospect of modulating the chain of events leading to cellular survival/damage may help to generate the potential strategies for neuroprotection. This review briefly covers the current status on the molecular mechanisms of stroke pathophysiology with an endeavour to identify potential molecular targets such as targeting postsynaptic density-95 (PSD-95)/N-methyl-d-aspartate (NMDA) receptor interaction, certain key proteins involved in oxidative stress, CaMKs and MAPKs (ERK, p38 and JNK) signalling, inflammation (cytokines, adhesion molecules, etc.) and cell death pathways (caspases, Bcl-2 family proteins, poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis-inducing factor (AIF), inhibitors of apoptosis proteins (IAPs), heat shock protein 70 (HSP70), receptor interacting protein (RIP), etc., besides targeting directly the genes itself. However, selecting promising targets from various signalling cascades, for drug discovery and development is very challenging, nevertheless such novel approaches may lead to the emergence of new avenues for therapeutic intervention in cerebral ischemia.
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              Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities.

              Carbon monoxide (CO) is generated in living organisms during the degradation of heme by the enzyme heme oxygenase, which exists in constitutive (HO-2 and HO-3) and inducible (HO-1) isoforms. Carbon monoxide gas is known to dilate blood vessels in a manner similar to nitric oxide and has been recently shown to possess antiinflammatory and antiapoptotic properties. We report that a series of transition metal carbonyls, termed here carbon monoxide-releasing molecules (CO-RMs), liberate CO to elicit direct biological activities. Specifically, spectrophotometric and NMR analysis revealed that dimanganese decacarbonyl and tricarbonyldichlororuthenium (II) dimer release CO in a concentration-dependent manner. Moreover, CO-RMs caused sustained vasodilation in precontracted rat aortic rings, attenuated coronary vasoconstriction in hearts ex vivo, and significantly reduced acute hypertension in vivo. These vascular effects were mimicked by induction of HO-1 after treatment of animals with hemin, which increases endogenously generated CO. Thus, we have identified a novel class of compounds that are useful as prototypes for studying the bioactivity of CO. In the long term, transition metal carbonyls could be utilized for the therapeutic delivery of CO to alleviate vascular- and immuno-related dysfunctions. The full text of this article is available at http://www.circresaha.org.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                20 October 2016
                2016
                : 11
                : 10
                : e0165182
                Affiliations
                [1 ]Department of Anesthesiology and Critical Care, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
                [2 ]Eye Center, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
                [3 ]Instituto de Tecnologia Química e Biológica-António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
                [4 ]Alfama Ltd., Instituto de Biologia Experimental e Tecnológica, IBET, Oeiras, Portugal
                Indian Institute of Science Education and Research, INDIA
                Author notes

                Competing Interests: We have the following interests: The co-author Carlos C. Romão is a co-founder, administrator and scientific officer of the company Alfama Lda. where he has equity interests. Carlos C. Romão is an inventor of Patent-No.: US 2011/0038955 A1 2011, where ALF-186 exemplifies the protection of the stomach against NSAID generated ulcers by the administration of CORMs, and is therefore irrelevant for the matter of the present article. The drug profile of ALF-186 is published in detail in: Dalton Transactions DOI: 10.1039/c2dt32174b. "Alfama Ltd. provided support in supplying C.C.R. with the ALF-186 compound, which is not commercially available. There are no further patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                • Conceptualization: JB UG.

                • Data curation: JB UG.

                • Formal analysis: FU KBK AM WAL MA HB CCR JB UG.

                • Funding acquisition: JB UG.

                • Investigation: FU KBK AM MA.

                • Methodology: WAL MA JB UG.

                • Project administration: JB UG.

                • Resources: WAL HB CCR JB UG.

                • Supervision: JB UG.

                • Validation: FU KBK AM WAL MA HB CCR JB UG.

                • Visualization: FU JB UG.

                • Writing – original draft: FU KBK AM WAL MA HB CCR JB UG.

                • Writing – review & editing: FU KBK AM WAL MA HB CCR JB UG.

                Author information
                http://orcid.org/0000-0002-9991-3226
                Article
                PONE-D-16-17732
                10.1371/journal.pone.0165182
                5072679
                27764224
                8ec941c7-fcdf-4334-b9b4-15742efe03de
                © 2016 Ulbrich et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 2 May 2016
                : 8 October 2016
                Page count
                Figures: 9, Tables: 0, Pages: 18
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: Go 2158/3-1
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: Bi 1567/2-1
                Award Recipient :
                Funded by: Alfama Ltd.
                Award Recipient :
                This work was conducted at the Department of Anesthesiology and Intensive Care, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany and granted by The German Research Foundation (DFG, Grants: Go 2158/3-1 and Bi 1567/2-1). The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Alfama Ltd. provided support in the form of supplying Carlos C. Romão with the ALF-186 compound - which is not commercially available - but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the 'author contributions' section.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Neurons
                Afferent Neurons
                Retinal Ganglion Cells
                Biology and Life Sciences
                Neuroscience
                Cellular Neuroscience
                Neurons
                Afferent Neurons
                Retinal Ganglion Cells
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Neurons
                Ganglion Cells
                Retinal Ganglion Cells
                Biology and Life Sciences
                Neuroscience
                Cellular Neuroscience
                Neurons
                Ganglion Cells
                Retinal Ganglion Cells
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Apoptosis
                Biology and Life Sciences
                Biochemistry
                Proteins
                Post-Translational Modification
                Phosphorylation
                Biology and life sciences
                Cell biology
                Signal transduction
                Cell signaling
                Signaling cascades
                MAPK signaling cascades
                Physical Sciences
                Chemistry
                Chemical Compounds
                Carbon Monoxide
                Biology and Life Sciences
                Anatomy
                Ocular System
                Ocular Anatomy
                Retina
                Medicine and Health Sciences
                Anatomy
                Ocular System
                Ocular Anatomy
                Retina
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Medicine and Health Sciences
                Vascular Medicine
                Ischemia
                Custom metadata
                All relevant data are within the paper.

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