Christiane Charriaut-Marlangue1, Thao Nguyen, Philippe Bonnin, An Phan Duy, Pierre-Louis Leger, Zsolt Csaba, Julien Pansiot, Thomas Bourgeois, Sylvain Renolleau, Olivier Baud. 1. From the Univ Paris Diderot, Sorbonne Paris Cité, INSERM U1141, Paris, France (C.C.-M., T.N., A.P.D., P.-L.L., Z.C., J.P., T.B., O.B.); PremUP Foundation, Paris, France (C.C.-M., P.-L.L., J.P., O.B.); Univ Paris Diderot, Sorbonne Paris Cité, AP-HP, Hôpital Lariboisière, Physiologie clinique - Explorations Fonctionnelles, Paris, France (P.B.); Univ Paris Diderot, Sorbonne Paris Cité, INSERM, U965, Paris, France (P.B.); UPMC, Paris Universitas, AP-HP, Hôpital Armand Trousseau, Service de Réanimation, pédiatrique, Paris, France (S.R.); and Univ Paris Diderot, Sorbonne Paris Cité, AP-HP Service de Réanimation et Pédiatrie Néonatales, Hôpital Robert Debré, Paris, France (O.B.).
Abstract
BACKGROUND AND PURPOSE: The best conceivable treatment for hypoxia-ischemia (HI) is the restoration of blood flow to the hypoxic-ischemic region(s). Our objective was to examine whether boosting NO-cGMP signaling using sildenafil citrate, a phosphodiesterase-type 5 inhibitor, could modify cerebral blood flow and reduce lesions in the developing brain. METHODS: HI was induced in P7 Sprague-Dawley rats by unilateral carotid artery occlusion and hypoxia, and followed by either PBS or sildenafil. Blood-flow velocities were measured by ultrasound imaging with sequential Doppler recordings to evaluate collateral recruitment. Cell death, blood-brain barrier integrity, and glial activation were analyzed by immunohistochemistry. Motor behavior was evaluated using an open-field device adapted to neonatal animals. RESULTS: Sildenafil citrate (10 mg/kg) induced collateral patency, reduced terminal dUTP nick-end labeling-positive cells, reactive astrogliosis, and macrophage/microglial activation at 72 hours and 7 days post-HI. Sildenafil also reduced the number of terminal dUTP nick-end labeling-positive endothelial cells within lesion site. Seven days after HI and sildenafil treatment, tissue loss was significantly reduced, and animals recovered motor coordination. CONCLUSIONS: Our findings strongly indicate that sildenafil citrate treatment, associated with a significant increase in cerebral blood flow, reduces HI damage and improves motor locomotion in neonatal rats. Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection.
BACKGROUND AND PURPOSE: The best conceivable treatment for hypoxia-ischemia (HI) is the restoration of blood flow to the hypoxic-ischemic region(s). Our objective was to examine whether boosting NO-cGMP signaling using sildenafil citrate, a phosphodiesterase-type 5 inhibitor, could modify cerebral blood flow and reduce lesions in the developing brain. METHODS:HI was induced in P7 Sprague-Dawley rats by unilateral carotid artery occlusion and hypoxia, and followed by either PBS or sildenafil. Blood-flow velocities were measured by ultrasound imaging with sequential Doppler recordings to evaluate collateral recruitment. Cell death, blood-brain barrier integrity, and glial activation were analyzed by immunohistochemistry. Motor behavior was evaluated using an open-field device adapted to neonatal animals. RESULTS:Sildenafil citrate (10 mg/kg) induced collateral patency, reduced terminal dUTP nick-end labeling-positive cells, reactive astrogliosis, and macrophage/microglial activation at 72 hours and 7 days post-HI. Sildenafil also reduced the number of terminal dUTP nick-end labeling-positive endothelial cells within lesion site. Seven days after HI and sildenafil treatment, tissue loss was significantly reduced, and animals recovered motor coordination. CONCLUSIONS: Our findings strongly indicate that sildenafil citrate treatment, associated with a significant increase in cerebral blood flow, reduces HI damage and improves motor locomotion in neonatal rats. Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection.
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