title: Nitric Oxide Production in the Striatum and Cerebellum of a Rat Model of Preterm Global Perinatal Asphyxia.
abstract: Encephalopathy due to perinatal asphyxia (PA) is a major cause of neonatal morbidity and mortality in the period around birth. Preterm infants are especially at risk for cognitive, attention and motor impairments. Therapy for this subgroup is limited to supportive care, and new targets are thus urgently needed. Post-asphyxic excitotoxicity is partially mediated by excessive nitric oxide (NO) release. The aims of this study were to determine the timing and distribution of nitric oxide (NO) production after global PA in brain areas involved in motor regulation and coordination. This study focused on the rat striatum and cerebellum, as these areas also affect cognition or attention, in addition to their central role in motor control. NO/peroxynitrite levels were determined empirically with a fluorescent marker on postnatal days P5, P8 and P12. The distributions of neuronal NO synthase (nNOS), cyclic guanosine monophosphate (cGMP), astroglia and caspase-3 were determined with immunohistochemistry. Apoptosis was additionally assessed by measuring caspase-3-like activity from P2-P15. On P5 and P8, increased intensity of NO-associated fluorescence and cGMP immunoreactivity after PA was apparent in the striatum, but not in the cerebellum. No changes in nNOS immunoreactivity or astrocytes were observed. Modest changes in caspase-3-activity were observed between groups, but the overall time course of apoptosis over the first 11 days of life was similar between PA and controls. Altogether, these data suggest that PA increases NO/peroxynitrite levels during the first week after birth within the striatum, but not within the cerebellum, without marked astrogliosis. Therapeutic benefits of interventions that reduce endogenous NO production would likely be greater during this time frame.
authors.affiliation: Department Pediatrics, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands.|Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands.|EURON - European Graduate School of Neuroscience, Maastricht, The Netherlands.|DST/NWU Preclinical Drug Development Platform, North-West University, Potchefstroom, South Africa.
authors.forename: M
authors.initials: M
authors.lastname: Barkhuizen
authors.affiliation: Department Pediatrics, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands.|Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands.|Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, Netherlands.
authors.forename: W D J
authors.initials: WD
authors.lastname: Van de Berg
authors.affiliation: Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: De Vente
authors.affiliation: Department Pediatrics, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands.
authors.forename: C E
authors.initials: CE
authors.lastname: Blanco
authors.affiliation: Department Pediatrics, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands.|EURON - European Graduate School of Neuroscience, Maastricht, The Netherlands.|Institute of Biomedicine, Faculty of Medicine, Catholic University of Guayaquil, Guayaquil, Ecuador.
authors.forename: A W D
authors.initials: AW
authors.lastname: Gavilanes
authors.affiliation: Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands. h.steinbusch@maastrichtuniversity.nl.|EURON - European Graduate School of Neuroscience, Maastricht, The Netherlands. h.steinbusch@maastrichtuniversity.nl.|Department of Translational Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 5800, 6212 AZ, Maastricht, The Netherlands. h.steinbusch@maastrichtuniversity.nl.
authors.forename: H W M
authors.initials: HW
authors.lastname: Steinbusch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001238:Asphyxia Neonatorum / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D049590:Postpartum Period / Q000378:metabolism; D011247:Pregnancy; D051381:Rats
chemical_list: D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D053148:Caspase 3; D006152:Cyclic GMP
keywords: Asphyxia; Neuronal nitric oxide synthase; Nitrosidative stress; Peroxynitrite; Selective vulnerability; cGMP