title: A nitric oxide donor reduces brain injury and enhances recovery of cerebral blood flow after hypoxia-ischemia in the newborn rat.
abstract: Nitric oxide (NO) released in response to hypoxia-ischemia (HI) in the newborn brain may mediate both protective and pathologic responses. We sought to determine whether pharmacologic increase of NO using an NO donor would reduce neurologic injury resulting from HI in the postnatal day 7 rat. We measured NO levels and CBF in the presence of either a NOS inhibitor, N-nitro-l-arginine methyl ester (L-NAME) or an NO donor (Z)-1-[N-(2-amino-ethyl)-N-(2-ammonio-ethyl)amino]diazen-1-ium-1,2-diolate (DETANONOate). Both inhibition of NOS and administration of an NO donor reduced neuropathologic injury after 7-day recovery. NO levels decreased in both ischemic and contralateral hemispheres during HI. This response was prevented by treatment with DETANONOate. Despite the decrease in NO, CBF increased during ischemia in the contralateral hemisphere but decreased when combined with brief hypoxia. Treatment with L-NAME abolished these increases, which were not altered by DETANONOate. Reduction of cellular metabolism by mild hypothermia also reduced both NO and CBF. Following prolonged HI, CBF remained decreased in the ischemic hemisphere up to 24-h recovery. This decrease was prevented by treatment with DETANONOate. These data show that administration of an NO donor reduces neurologic injury following HI in the newborn rat. This mechanism of this protection, in part, is due to an increase in the rate of recovery of CBF compared to vehicle-treated animals. Augmentation of NO-dependent increases in CBF may serve to improve neurologic outcome after perinatal asphyxia.
authors.affiliation: Department of Pediatrics, Division of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60614, USA. m-wainwright@northwestern.edu
authors.forename: Mark S
authors.initials: MS
authors.lastname: Wainwright
authors.forename: Dava
authors.initials: D
authors.lastname: Grundhoefer
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology; D002545:Brain Ischemia / Q000150:complications; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007839:Functional Laterality / Q000187:drug effects; D017078:Laser-Doppler Flowmetry / Q000379:methods; D015227:Lipid Peroxidation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D009603:Nitroso Compounds / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects*
chemical_list: D000447:Aldehydes; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; C027576:4-hydroxy-2-nonenal; D019331:NG-Nitroarginine Methyl Ester