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J Neuroinflammation. 2016 Apr 28;13(1):95. doi: 10.1186/s12974-016-0560-4.

Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain.

Author information

1
University Paris Diderot, Sorbonne Paris Cité, INSERM, UMR 1141, 75019, Paris, France.
2
University degli Studi di Udine, Udine, Italy.
3
UPMC-Paris6, AP-HP, Hôpital Armand Trousseau, Réanimation Néonatale et Pédiatrique, 75012, Paris, France.
4
Pharmacologie de la Circulation Cérébrale - EA4475, Faculté des Sciences Pharmaceutiques et Biologiques, University of Paris Descartes, Paris, France.
5
University Paris Diderot, Sorbonne Paris Cité, AP-HP, Hôpital Robert Debré, Urgences Pédiatriques, 75019, Paris, France.
6
University Paris Diderot, Sorbonne Paris Cité, AP-HP, Hôpital Lariboisière, Physiologie Clinique, Explorations-Fonctionnelles, 75010, Paris, France.
7
University Paris Diderot, Sorbonne Paris Cité, INSERM, U965, 75010, Paris, France.
8
University Paris Diderot, Sorbonne Paris Cité, AP-HP, Hôpital Robert Debré, Réanimation Néonatale, 75019, Paris, France.
9
University Paris Diderot, Sorbonne Paris Cité, INSERM, UMR 1141, 75019, Paris, France. christiane.marlangue@gmail.com.
10
INSERM UMR 1141, Hopital Robert Debré, 48 bd Serurier, 75019, Paris, France. christiane.marlangue@gmail.com.

Abstract

BACKGROUND:

Perinatal ischemic stroke is the most frequent form of cerebral infarction in neonates; however, evidence-based treatments are currently lacking. We have previously demonstrated a beneficial effect of sildenafil citrate, a PDE-5 inhibitor, on stroke lesion size in neonatal rat pups. The present study investigated the effects of sildenafil in a neonatal mouse stroke model on (1) hemodynamic changes and (2) regulation of astrocyte/microglia-mediated neuroinflammation.

METHODS:

Ischemia was induced in C57Bl/6 mice on postnatal (P) day 9 by permanent middle cerebral artery occlusion (pMCAo), and followed by either PBS or sildenafil intraperitoneal (i.p.) injections. Blood flow (BF) velocities were measured by ultrasound imaging with sequential Doppler recordings and laser speckle contrast imaging. Animals were euthanized, and brain tissues were obtained at 72 h or 8 days after pMCAo. Expression of M1- and M2-like microglia/macrophage markers were analyzed.

RESULTS:

Although sildenafil (10 mg/kg) treatment potently increased cGMP concentrations, it did not influence early collateral recruitment nor did it reduce mean infarct volumes 72 h after pMCAo. Nevertheless, it provided a significant dose-dependent reduction of mean lesion extent 8 days after pMCAo. Suggesting a mechanism involving modulation of the inflammatory response, sildenafil significantly decreased microglial density at 72 h and 8 days after pMCAo. Gene expression profiles indicated that sildenafil treatment also modulates M1- (ptgs2, CD32 and CD86) and M2-like (CD206, Arg-1 and Lgals3) microglia/macrophages in the late phase after pMCAo. Accordingly, the number of COX-2(+) microglia/macrophages significantly increased in the penumbra at 72 h after pMCAo but was significantly decreased 8 days after ischemia in sildenafil-treated animals.

CONCLUSIONS:

Our findings argue that anti-inflammatory effects of sildenafil may provide protection against lesion extension in the late phase after pMCAo in neonatal mice. We propose that sildenafil treatment could represent a potential strategy for neonatal ischemic stroke treatment/recovery.

KEYWORDS:

Focal ischemia; M2 microglia; Microcirculation; Microglia; Neonatal mice

PMID:
27126393
PMCID:
PMC4850658
DOI:
10.1186/s12974-016-0560-4
[Indexed for MEDLINE]
Free PMC Article

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