This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Peeters-Scholte, C. Articles by Groenendaal, F. Search for Related Content PubMed PubMed Citation Articles by Peeters-Scholte, C. Articles by Groenendaal, F. Related Collections Animal models of human disease Brain Circulation and Metabolism Neuroprotectors

(Stroke. 2002;33:2304.)
© 2002 American Heart Association, Inc.

Original Contributions

Neuroprotection by Selective Nitric Oxide Synthase Inhibition at 24 Hours After Perinatal Hypoxia-Ischemia

Cacha Peeters-Scholte, MD; Johanna Koster, PhD; Wouter Veldhuis, MSc; Evelyn van den Tweel, MSc; Changlian Zhu, PhD; Nicole Kops; Klas Blomgren, MD, PhD; Dop Bär, PhD; Sylvia van Buul-Offers, PhD; Hendrik Hagberg, MD, PhD; Klaas Nicolay, PhD; Frank van Bel, MD, PhD Floris Groenendaal, MD, PhD

From the Department of Neonatology, Wilhelmina Children’s Hospital (C.P-S., J.K., E. van den T., F. van B., F.G.); Department of Experimental In Vivo Nuclear Magnetic Resonance, Image Sciences Institute (W.V., K.N.); Departments of Experimental Neurology (D.B.) and Pediatric Endocrinology (N.K., S. van B-O.), University Medical Center Utrecht, Utrecht, Netherlands; and Perinatal Center, Institute of Physiology and Pharmacology, Göteborg University, Göteborg, Sweden (C.Z., K.B., H.H.).

Reprint requests to F. Groenendaal, MD, PhD, Wilhelmina Children’s Hospital/University Medical Center Utrecht, Department of Neonatology, Room KE.04.123.1, PO Box 85090, 3508 AB Utrecht, Netherlands. E-mail F.Groenendaal{at}wkz.azu.nl

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.

Key Words: caspases • cerebral ischemia, global • magnetic resonance imaging • neuroprotection • reperfusion injury • spectroscopy, nuclear magnetic resonance

This article has been cited by other articles:

				F Groenendaal, H Lammers, D Smit, and P G J Nikkels Nitrotyrosine in brain tissue of neonates after perinatal asphyxia Arch. Dis. Child. Fetal Neonatal Ed., November 1, 2006; 91(6): F429 - F433. [Abstract] [Full Text] [PDF]

				K. M. Tichauer, D. W. Brown, J. Hadway, T.-Y. Lee, and K. St. Lawrence Near-infrared spectroscopy measurements of cerebral blood flow and oxygen consumption following hypoxia-ischemia in newborn piglets J Appl Physiol, March 1, 2006; 100(3): 850 - 857. [Abstract] [Full Text] [PDF]

				M. C. Toet, P. M.A. Lemmers, L. J. van Schelven, and F. van Bel Cerebral Oxygenation and Electrical Activity After Birth Asphyxia: Their Relation to Outcome Pediatrics, February 1, 2006; 117(2): 333 - 339. [Abstract] [Full Text] [PDF]

				X. Wei, L. Zhao, Z. Ma, D. M. Holtzman, C. Yan, R. C. Dodel, H. Hampel, W. Oertel, M. R. Farlow, and Y. Du Caffeic acid phenethyl ester prevents neonatal hypoxic-ischaemic brain injury Brain, December 1, 2004; 127(12): 2629 - 2635. [Abstract] [Full Text] [PDF]

				D. M. Ferriero Neonatal Brain Injury N. Engl. J. Med., November 4, 2004; 351(19): 1985 - 1995. [Full Text] [PDF]