| Title: |
Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain |
| Authors: |
Moretti, Raffaella; Leger, Pierre-Louis; Besson, Valérie, C.; Csaba, Zsolt; Pansiot, Julien; Di Criscio, Lorena; Gentili, Andrea; Titomanlio, Luigi; Bonnin, Philippe; Baud, Olivier; Charriaut-Marlangue, Christiane |
| Contributors: |
Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM); Clinica Pediatrica – Ospedale di Udine; Università degli Studi di Udine - University of Udine Italie; CHU Trousseau APHP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU); Pharmacologie de la circulation cérébrale (EA 4475); Université Paris Descartes - Paris 5 (UPD5); AP-HP, Hôpital Robert Debré, Pôle de Pédiatrie Aiguë et Médecine Interne, Service d'Accueil des Urgences Pédiatriques; Université Paris Diderot - Paris 7 (UPD7); Carcinose Angiogenèse et Recherche Translationnelle; Angiogenese et recherche translationnelle (CART U965); Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM); Physiologie Clinique, Explorations-Fonctionnelles; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal APHP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité; Réanimation et Pédiatrie Néonatales; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7); INSERM |
| Source: |
ISSN: 1742-2094 ; Journal of Neuroinflammation ; https://inserm.hal.science/inserm-01316302 ; Journal of Neuroinflammation, 2016, ⟨10.1186/s12974-016-0560-4⟩. |
| Publisher Information: |
CCSD; BioMed Central |
| Publication Year: |
2016 |
| Subject Terms: |
Neonatal mice; Focal ischemia; Microglia; M2 microglia; Microcirculation; [SDV.BC]Life Sciences [q-bio]/Cellular Biology; [SDV.BDD]Life Sciences [q-bio]/Development Biology |
| Description: |
International audience ; 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 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1186/s12974-016-0560-4 |
| Availability: |
https://inserm.hal.science/inserm-01316302; https://inserm.hal.science/inserm-01316302v1/document; https://inserm.hal.science/inserm-01316302v1/file/Moretti%20et%20al-2016.pdf; https://doi.org/10.1186/s12974-016-0560-4 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.F9AC911A |
| Database: |
BASE |