title: Dose-dependent effects of levetiracetam after hypoxia and hypothermia in the neonatal mouse brain.
abstract: Perinatal asphyxia to the developing brain remains a major cause of morbidity. Hypothermia is currently the only established neuroprotective treatment available for term born infants with hypoxic-ischemic encephalopathy, saving one in seven to eight infants from developing severe neurological deficits. Therefore, additional treatments with clinically applicable drugs are indispensable. This study investigates a potential additive neuroprotective effect of levetiracetam combined with hypothermia after hypoxia-induced brain injury in neonatal mice. 9-day-old C57BL/6-mice (P9) were subjected either to acute hypoxia or room-air. After 90min of systemic hypoxia (6% O2), pups were randomized into six groups: 1) vehicle, 2) low-dose levetiracetam (LEV), 3) high-dose LEV, 4) hypothermia (HT), 5) HT combined with low-dose LEV and 6) HT combined with high-dose LEV. Pro-apoptotic factors, neuronal structures, and myelination were analysed by histology and on protein level at appropriate time points. On P28 to P37 long-term outcome was assessed by neurobehavioral testing. Hypothermia confers acute and long-term neuroprotection by reducing apoptosis and preservation of myelinating oligodendrocytes and neurons in a model of acute hypoxia in the neonatal mouse brain. Low-dose LEV caused no adverse effects after neonatal hypoxic brain damage treated with hypothermia whereas administration of high-dose LEV alone or in combination with hypothermia increased neuronal apoptosis after hypoxic brain injury. LEV in low- dosage had no additive neuroprotective effect following acute hypoxic brain injury.
authors.affiliation: Department of Pediatrics 1, Neonatology, Un iversity Hospital Essen, University Duisburg, Essen, Germany; Department of Pediatrics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Strasser
authors.affiliation: Department of Pediatrics 1, Neonatology, Un iversity Hospital Essen, University Duisburg, Essen, Germany; Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Lueckemann
authors.affiliation: Department of Pediatrics 1, Neonatology, Un iversity Hospital Essen, University Duisburg, Essen, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Kluever
authors.affiliation: Department of Pediatrics 1, Neonatology, Un iversity Hospital Essen, University Duisburg, Essen, Germany.
authors.forename: Sinthuya
authors.initials: S
authors.lastname: Thavaneetharajah
authors.affiliation: Department of Pediatrics 1, Neonatology, Un iversity Hospital Essen, University Duisburg, Essen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Hoeber
authors.affiliation: Department of Pediatrics 1, Neonatology, Un iversity Hospital Essen, University Duisburg, Essen, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Bendix
authors.affiliation: Institute of Physiology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
authors.affiliation: Department of Pediatrics 1, Neonatology, Un iversity Hospital Essen, University Duisburg, Essen, Germany; Department of Women and Child Health, University Hospital for Children and Adolescents, Centre for Pediatric Research Leipzig, Germany. Electronic address: Astrid.Bertsche@medizin.uni-leipzig.de.
authors.forename: Astrid
authors.initials: A
authors.lastname: Bertsche
authors.affiliation: Department of Pediatrics 1, Neonatology, Un iversity Hospital Essen, University Duisburg, Essen, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Felderhoff-Mueser
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000627:therapeutic use; D001007:Anxiety; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007036:Hypothermia, Induced; D000860:Hypoxia / Q000150:complications*; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology; D010889:Piracetam / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D021641:Recognition, Psychology / Q000187:drug effects; D045442:Rotarod Performance Test
chemical_list: D000927:Anticonvulsants; D018696:Neuroprotective Agents; D000077287:Levetiracetam; D010889:Piracetam
keywords: Apoptosis; Hypothermia; Levetiracetam; Neonatal mice; Neuroprotection; Perinatal asphyxia