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

Abstract

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 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.

• Authors: Cacha Peeters-Scholte, Johanna Koster, Wouter Veldhuis, Evelyn van den Tweel, Changlian Zhu, Nicole Kops, Klas Blomgren, Dop Bär, Sylvia van Buul-Offers, Hendrik Hagberg, Klaas Nicolay, Frank van Bel, Floris Groenendaal
• Journal: Stroke (Stroke) Vol. 33 Issue 9 Pg. 2304-10 (Sep 2002) ISSN: 1524-4628 [Electronic] United States
• PMID: 12215603 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Neuroprotective Agents
• Tyrosine
• Biotin
• Nitric Oxide Synthase
• Caspase 3
• Caspases
• 2-iminobiotin

Topics

• Animals
• Animals, Newborn
• Apoptosis (drug effects)
• Biotin (analogs & derivatives, pharmacology)
• Brain (blood supply, drug effects, pathology, physiopathology)
• Brain Edema (etiology, pathology, prevention & control)
• Caspase 3
• Caspases (metabolism)
• Disease Models, Animal
• Energy Metabolism (drug effects)
• Enzyme Inhibitors (pharmacology)
• Hypoxia-Ischemia, Brain (complications, drug therapy, physiopathology)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Magnetic Resonance Spectroscopy
• Neuroprotective Agents (pharmacology)
• Nitric Oxide Synthase (antagonists & inhibitors)
• Reperfusion Injury (etiology, pathology, prevention & control)
• Survival Rate
• Swine
• Treatment Outcome
• Tyrosine (metabolism)