title: nNOS inhibition during profound asphyxia reduces seizure burden and improves survival of striatal phenotypic neurons in preterm fetal sheep.
abstract: Basal ganglia injury after hypoxia-ischemia remains common in preterm infants, and is closely associated with later cerebral palsy. In the present study we tested the hypothesis that a highly selective neuronal nitric oxide synthase (nNOS) inhibitor, JI-10, would improve survival of striatal phenotypic neurons after profound asphyxia, and that the subsequent seizure burden and recovery of EEG are associated with neural outcome. 24 chronically instrumented preterm fetal sheep were randomized to either JI-10 (3 ml of 0.022 mg/ml, n = 8) or saline (n = 8) infusion 15 min before 25 min complete umbilical cord occlusion, or saline plus sham-occlusion (n = 8). Umbilical cord occlusion was associated with reduced numbers of calbindin-28k-, GAD-, NPY-, PV-, Calretinin- and nNOS-positive striatal neurons (p < 0.05 vs. sham occlusion) but not ChAT-positive neurons. JI-10 was associated with increased numbers of calbindin-28k-, GAD-, nNOS-, NPY-, PV-, Calretinin- and ChAT-positive striatal neurons (p < 0.05 vs. saline + occlusion). Seizure burden was strongly associated with loss of calbindin-positive cells (p < 0.05), greater seizure amplitude was associated with loss of GAD-positive cells (p < 0.05), and with more activated microglia in the white matter tracts (p < 0.05). There was no relationship between EEG power after 7 days recovery and total striatal cell loss, but better survival of NPY-positive neurons was associated with lower EEG power. In summary, these findings suggest that selective nNOS inhibition during asphyxia is associated with protection of phenotypic striatal projection neurons and has potential to help reduce basal ganglia injury in some premature babies.
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Drury
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Joanne O
authors.initials: JO
authors.lastname: Davidson
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Sam
authors.initials: S
authors.lastname: Mathai
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Lotte G
authors.initials: LG
authors.lastname: van den Heuij
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA; Department of Chemistry, University of Utah, Salt Lake City, UT, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Laura
authors.initials: L
authors.lastname: Bennet
authors.affiliation: Department of Pediatrics, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand. Electronic address: aj.gunn@auckland.ac.nz.
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Gunn
mesh_terms: D000631:Aminopyridines / Q000627:therapeutic use*; D000818:Animals; D001237:Asphyxia / Q000150:complications* / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005311:Fetal Hypoxia / Q000503:physiopathology; D005333:Fetus; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D010641:Phenotype; D011247:Pregnancy; D047928:Premature Birth; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology / Q000532:radiotherapy; D012756:Sheep
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D052248:Nitric Oxide Synthase Type I
keywords: Asphyxia; Basal ganglia; Neuroprotection; Preterm fetus; Seizures; nNOS
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