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

Background and Purpose-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 Methods-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 m k end labeling (TUNEL)-positive cells and degree of tyrosine nitration were assessed Results-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 ortex was observed in 2 iminobiotin-treated piglets indicating decreased formation of reactive nitrogen species Conclusions-Simultaneous and selective inhibition of neuronal and inducible nitric oxide synthase by 2 iminobiotin is a promising strategy for neuroprotection after perinatal hypoxia ischemia.