title: Partial neuroprotection by nNOS inhibition during profound asphyxia in preterm fetal sheep.
abstract: Preterm brain injury is partly associated with hypoxia-ischemia starting before birth. Excessive nitric oxide production during HI may cause nitrosative stress, leading to cell membrane and mitochondrial damage. We therefore tested the hypothesis that therapy with a new, selective neuronal nitric oxide synthase (nNOS) inhibitor, JI-10 (0.022mg/kg bolus, n=8), given 30min before 25min of complete umbilical cord occlusion was protective in preterm fetal sheep at 101-104day gestation (term is 147days), compared to saline (n=8). JI-10 had no effect on fetal blood pressure, heart rate, carotid and femoral blood flow, total EEG power, nuchal activity, temperature or intracerebral oxygenation on near-infrared spectroscopy during or after occlusion. JI-10 was associated with later onset of post-asphyxial seizures compared with saline (p<0.05), and attenuation of the subsequent progressive loss of cytochrome oxidase (p<0.05). After 7days recovery, JI-10 was associated with improved neuronal survival in the caudate nucleus (p<0.05), but not the putamen or hippocampus, and more CNPase positive oligodendrocytes in the periventricular white matter (p<0.05). In conclusion, prophylactic nNOS inhibition before profound asphyxia was associated with delayed onset of seizures, slower decline of cytochrome oxidase and partial white and gray matter protection, consistent with protection of mitochondrial function.
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand. Electronic address: p.drury@auckland.ac.nz.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Drury
authors.forename: Joanne O
authors.initials: JO
authors.lastname: Davidson
authors.forename: Lotte G
authors.initials: LG
authors.lastname: van den Heuij
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Tan
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Blood
authors.forename: Mhoyra
authors.initials: M
authors.lastname: Fraser
authors.forename: Laura
authors.initials: L
authors.lastname: Bennet
authors.forename: Alistair Jan
authors.initials: AJ
authors.lastname: Gunn
mesh_terms: D000818:Animals; D002547:Cerebral Palsy / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005311:Fetal Hypoxia / Q000150:complications* / Q000201:enzymology; D005333:Fetus; D020925:Hypoxia-Ischemia, Brain / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology / Q000517:prevention & control*; D012640:Seizures / Q000209:etiology / Q000517:prevention & control; D012756:Sheep
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D052248:Nitric Oxide Synthase Type I
keywords: Asphyxia; Brain; Neuroprotection; Preterm fetus; nNOS