Neuroprotection by selective nitric oxide synthase inhibition at 24 hours after perinatal hypoxia-ischemia.
OBJECTIVE
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 nick 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 cortex 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.
Peeters-Scholte
Cacha
C
Department of Neonatology, Wilhelmina Children's Hospital, Utrecht, Netherlands.
Koster
Johanna
J
Veldhuis
Wouter
W
van den Tweel
Evelyn
E
Zhu
Changlian
C
Kops
Nicole
N
Blomgren
Klas
K
Bär
Dop
D
van Buul-Offers
Sylvia
S
Hagberg
Hendrik
H
Nicolay
Klaas
K
van Bel
Frank
F
Groenendaal
Floris
F
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001710:Biotin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009682:Magnetic Resonance Spectroscopy; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015996:Survival Rate; D013552:Swine; D016896:Treatment Outcome; D014443:Tyrosine / Q000378:metabolism
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D014443:Tyrosine; D001710:Biotin; D019001:Nitric Oxide Synthase; D053148:Caspase 3; D020169:Caspases; C028072:2-iminobiotin