title: The common antitussive agent dextromethorphan protects against hyperoxia-induced cell death in established in vivo and in vitro models of neonatal brain injury.
abstract: Preterm infants are prematurely subjected to relatively high oxygen concentrations, even when supplemental oxygen is not administered. There is increasing evidence to show that an excess of oxygen is toxic to the developing brain. Dextromethorphan (DM), a frequently used antitussive agent with pleiotropic mechanisms of action, has been shown to be neuroprotective in various models of central nervous system pathology. Due to its numerous beneficial properties, it might also be able to counteract detrimental effects of a neonatal oxygen insult. The aim of the current study was to evaluate its therapeutic potential in established cell culture and rodent models of hyperoxia-induced neonatal brain injury. For in vitro studies pre- and immature oligodendroglial (OLN-93) cells were subjected to hyperoxic conditions for 48 h after pre-treatment with increasing doses of DM. For in vivo studies 6-day-old Wistar rat pups received a single intraperitoneal injection of DM in two different dosages prior to being exposed to hyperoxia for 24h. Cell viability and caspase-3 activation were assessed as outcome parameters at the end of exposure. DM significantly increased cell viability in immature oligodendroglial cells subjected to hyperoxia. In pre-oligodendroglial cells cell viability was not significantly affected by DM treatment. In vivo caspase-3 activation induced by hyperoxic exposure was significantly lower after administration of DM in gray and white matter areas. In control animals kept under normoxic conditions DM did not significantly influence caspase-3-dependent apoptosis. The present results indicate that DM is a promising and safe treatment strategy for neonatal hyperoxia-induced brain injury that merits further investigation.
authors.affiliation: Department of Pediatrics II (Neonatology), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Posod
authors.affiliation: Department of Pediatrics II (Neonatology), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Pinzer
authors.affiliation: Department of Pediatrics II (Neonatology), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Urbanek
authors.affiliation: Department of Pediatrics II (Neonatology), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Wegleiter
authors.affiliation: Department of Pediatrics II (Neonatology), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria; Kinderklinik Dritter Orden, Technical University Munich, Bischof Altmann-Street 9, 94032 Passau, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Keller
authors.affiliation: Department of Pediatrics II (Neonatology), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: U
authors.initials: U
authors.lastname: Kiechl-Kohlendorfer
authors.affiliation: Department of Pediatrics II (Neonatology), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria. Electronic address: Elke.Griesmaier@i-med.ac.at.
authors.forename: E
authors.initials: E
authors.lastname: Griesmaier
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000996:Antitussive Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000633:toxicity; D003915:Dextromethorphan / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D066128:Gray Matter / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D018496:Hyperoxia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D010100:Oxygen / Q000378:metabolism; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism; D066127:White Matter / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D000097605:Sigma-1 Receptor
chemical_list: D000996:Antitussive Agents; D053148:Caspase 3; D016207:Cytokines; D003915:Dextromethorphan; D018696:Neuroprotective Agents; D010100:Oxygen; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C505410:Casp3 protein, rat
keywords: OLN-93; dextromethorphan; hyperoxia; neonatal brain injury; oxygen toxicity; sigma receptor