Neuroprotection by selective nitric oxide synthase inhibition at 24 hours after perinatal hypoxia-ischemia

• Published in: Stroke (1970) 2002-09, Vol.33 (9), p.2304-2310
• Main Authors: PEETERS-SCHOLTE, Cacha, KOSTER, Johanna, NICOLAY, Klaas, VAN BEL, Frank, GROENENDAAL, Floris, VELDHUIS, Wouter, VAN DEN TWEEL, Evelyn, CHANGLIAN ZHU, KOPS, Nicole, BLOMGREN, Klas, BÄR, Dop, VAN BUUL-OFFERS, Sylvia, HAGBERG, Hendrik
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Apoptosis - drug effects; Biological and medical sciences; Biotin - analogs & derivatives; Biotin - pharmacology; Brain - blood supply; Brain - drug effects; Brain - pathology; Brain - physiopathology; Brain Edema - etiology; Brain Edema - pathology; Brain Edema - prevention & control; Caspase 3; Caspases - metabolism; Disease Models, Animal; Energy Metabolism - drug effects; Enzyme Inhibitors - pharmacology; Hypoxia-Ischemia, Brain - complications; Hypoxia-Ischemia, Brain - drug therapy; Hypoxia-Ischemia, Brain - physiopathology; Immunohistochemistry; In Situ Nick-End Labeling; Magnetic Resonance Spectroscopy; Medical sciences; Medicin och hälsovetenskap; Neurology; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - pharmacology; Nitric Oxide Synthase - antagonists & inhibitors; Pharmacology. Drug treatments; Reperfusion Injury - etiology; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; Survival Rate; Swine; Treatment Outcome; Tyrosine - metabolism; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0039-2499; 1524-4628; 1524-4628
• DOI: 10.1161/01.STR.0000028343.25901.09

Perinatal hypoxia-ischemia is a major cause of neonatal morbidity and mortality. Until now no established neuroprotective intervention after perinatal hypoxia-ischemia has been available. The delay in cell death after perinatal hypoxia-ischemia creates possibilities for therapeutic intervention after the initial insult. Excessive nitric oxide and reactive oxygen species generated on hypoxia-ischemia and reperfusion play a key role in the neurotoxic cascade. The present study examines the neuroprotective properties of neuronal and inducible but not endothelial nitric oxide synthase inhibition by 2-iminobiotin in a piglet model of perinatal hypoxia-ischemia. Twenty-three newborn piglets were subjected to 60 minutes of hypoxia-ischemia, followed by 24 hours of reperfusion and reoxygenation. Five additional piglets served as sham-operated controls. On reperfusion, piglets were randomly treated with either vehicle (n=12) or 2-iminobiotin (n=11). At 24 hours after hypoxia-ischemia, the cerebral energy state, presence of vasogenic edema, amount of apparently normal neuronal cells, caspase-3 activity, amount of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL)-positive cells, and degree of tyrosine nitration were assessed. A 90% improvement in cerebral energy state, 90% reduction in vasogenic edema, and 60% to 80% reduction in apoptosis-related neuronal cell death were demonstrated in 2-iminobiotin-treated piglets at 24 hours after hypoxia- ischemia. A significant reduction in tyrosine nitration in the cerebral cortex was observed in 2-iminobiotin-treated piglets, indicating decreased formation of reactive nitrogen species. Simultaneous and selective inhibition of neuronal and inducible nitric oxide synthase by 2-iminobiotin is a promising strategy for neuroprotection after perinatal hypoxia-ischemia.