Sildenafil mediates blood-flow redistribution and neuroprotection after neonatal hypoxia-ischemia.
OBJECTIVE
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.
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.).
Christiane
C
Charriaut-Marlangue
Thao
T
Nguyen
Philippe
P
Bonnin
An Phan
AP
Duy
Pierre-Louis
PL
Leger
Zsolt
Z
Csaba
Julien
J
Pansiot
Thomas
T
Bourgeois
Sylvain
S
Renolleau
Olivier
O
Baud
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D006152:Cyclic GMP / Q000502:physiology; D007839:Functional Laterality / Q000502:physiology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D008833:Microcirculation / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects; D018696:Neuroprotective Agents; D009569:Nitric Oxide / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D051381:Rats; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*
D018696:Neuroprotective Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D006152:Cyclic GMP
neonatal stroke; nitric oxide; sildenafil