title: Neuroprotection by Caffeine in Hyperoxia-Induced Neonatal Brain Injury.
abstract: Sequelae of prematurity triggered by oxidative stress and free radical-mediated tissue damage have coined the term "oxygen radical disease of prematurity". Caffeine, a potent free radical scavenger and adenosine receptor antagonist, reduces rates of brain damage in preterm infants. In the present study, we investigated the effects of caffeine on oxidative stress markers, anti-oxidative response, inflammation, redox-sensitive transcription factors, apoptosis, and extracellular matrix following the induction of hyperoxia in neonatal rats. The brain of a rat pups at postnatal Day 6 (P6) corresponds to that of a human fetal brain at 28-32 weeks gestation and the neonatal rat is an ideal model in which to investigate effects of oxidative stress and neuroprotection of caffeine on the developing brain. Six-day-old Wistar rats were pre-treated with caffeine and exposed to 80% oxygen for 24 and 48 h. Caffeine reduced oxidative stress marker (heme oxygenase-1, lipid peroxidation, hydrogen peroxide, and glutamate-cysteine ligase catalytic subunit (GCLC)), promoted anti-oxidative response (superoxide dismutase, peroxiredoxin 1, and sulfiredoxin 1), down-regulated pro-inflammatory cytokines, modulated redox-sensitive transcription factor expression (Nrf2/Keap1, and NFκB), reduced pro-apoptotic effectors (poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis inducing factor (AIF), and caspase-3), and diminished extracellular matrix degeneration (matrix metalloproteinases (MMP) 2, and inhibitor of metalloproteinase (TIMP) 1/2). Our study affirms that caffeine is a pleiotropic neuroprotective drug in the developing brain due to its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.
authors.affiliation: Department of Neonatology, Charité, Universitätsmedizin Berlin, 13353 Berlin, Germany. stefanie.endesfelder@charite.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Endesfelder
authors.affiliation: Department of Physiology, Charité, Universitätsmedizin Berlin, 10117 Berlin, Germany. ulrike.weichelt@charite.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Weichelt
authors.affiliation: Department of Neonatology, Charité, Universitätsmedizin Berlin, 13353 Berlin, Germany. evelyn.strauss@charite.de.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Strauß
authors.affiliation: Department of Biochemistry and Biology, University of Potsdam, 14476 Potsdam, Germany. anja.schloer@uni-potsdam.de.
authors.forename: Anja
authors.initials: A
authors.lastname: Schlör
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Charité, Universitätsmedizin Berlin, 13353 Berlin, Germany. marco.sifringer@charite.de.
authors.forename: Marco
authors.initials: M
authors.lastname: Sifringer
authors.affiliation: Department of Neonatology, Charité, Universitätsmedizin Berlin, 13353 Berlin, Germany. till.scheuer@charite.de.
authors.forename: Till
authors.initials: T
authors.lastname: Scheuer
authors.affiliation: Department of Neonatology, Charité, Universitätsmedizin Berlin, 13353 Berlin, Germany. christoph.buehrer@charite.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bührer
authors.affiliation: Department of Neonatology, Charité, Universitätsmedizin Berlin, 13353 Berlin, Germany. thomas.schmitz@charite.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmitz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018496:Hyperoxia / Q000150:complications* / Q000188:drug therapy*; D007249:Inflammation / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000378:metabolism; D054464:Peroxiredoxins / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism; D017208:Rats, Wistar; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D016207:Cytokines; D016328:NF-kappa B; D018696:Neuroprotective Agents; D014157:Transcription Factors; D002110:Caffeine; D010958:Plasminogen; D054464:Peroxiredoxins; D052247:Nitric Oxide Synthase Type II; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010959:Tissue Plasminogen Activator; D020782:Matrix Metalloproteinases
keywords: anti-oxidative response; caffeine; developing brain; hyperoxia; oxidative stress; preterm infants