Cyclooxygenase-2-Derived Prostaglandins Mediate Cerebral Microcirculation in a Juvenile Ischemic Rat Model.
We previously showed that the selective neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) increases cerebral microcirculation in a juvenile ischemic rat model. We address the roles of cyclooxygenase (COX)-elaborated prostaglandins in collateral recruitment and blood supply.



Fourteen-day-old rats were subjected to ischemia-reperfusion and treated with either PBS or 7-NI (25 mg/kg) at the reperfusion onset. Six-keto-prostaglandin F1αwas measured using ELISA. COX-1 and COX-2 and prostaglandin terminal synthesizing enzymes were evaluated using reverse-transcriptase polymerase chain reaction and immunofluorescence. Microvascular blood flow indexes (artery diameter and capillaries number) were measured using sidestream dark-field videomicroscopy in PBS- and 7-NI-treated ischemic rats in the absence or presence of the COX-2 inhibitor NS-398 (5 mg/kg). Cell death was measured with the TUNEL (terminal transferase dUTP nick end labeling) assay and cleaved-caspase-3 immunostaining.



Six-keto-prostaglandin F1αand COX-2, associated with a prostaglandin E synthase, were significantly increased in PBS- and 7-NI-treated animals 15 minutes and 1 hour after ischemia-reperfusion, respectively. In contrast and as compared with PBS, 7-NI significantly decreased prostacyclin synthase and cytosolic prostaglandins E synthase mRNA. Selective COX-2 inhibition significantly decreased blood flow indexes and significantly reversed the effects of 7-NI, including the number of TUNEL+- and cleaved-caspase-3+-nuclei.



These results show that the juvenile rat brains mostly respond to ischemia by a COX-2-dependent prostaglandins production and suggest that the transcriptional responses observed under 7-NI facilitate and reorient COX-2-dependent prostaglandins production.
From the PROTECT, INSERM, University Paris Diderot, France (P.-L.L., J.P., V.B., O.B., C.C.-M.); UPMC, AP-HP, Hôpital Armand Trousseau, PICU, Paris, France (P.-L.L.); Pharmacologie de la Circulation Cérébrale-EA4475, University Paris Descartes, Faculté de Pharmacie, France (V.B., B.P.); University Rene Descartes, AP-HP, Hôpital Necker, PICU, Paris, France (S.R.); Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), Paris, France (B.C.).
Pierre-Louis
PL
Leger
From the PROTECT, INSERM, University Paris Diderot, France (P.-L.L., J.P., V.B., O.B., C.C.-M.); UPMC, AP-HP, Hôpital Armand Trousseau, PICU, Paris, France (P.-L.L.); Pharmacologie de la Circulation Cérébrale-EA4475, University Paris Descartes, Faculté de Pharmacie, France (V.B., B.P.); University Rene Descartes, AP-HP, Hôpital Necker, PICU, Paris, France (S.R.); Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), Paris, France (B.C.).
Julien
J
Pansiot
From the PROTECT, INSERM, University Paris Diderot, France (P.-L.L., J.P., V.B., O.B., C.C.-M.); UPMC, AP-HP, Hôpital Armand Trousseau, PICU, Paris, France (P.-L.L.); Pharmacologie de la Circulation Cérébrale-EA4475, University Paris Descartes, Faculté de Pharmacie, France (V.B., B.P.); University Rene Descartes, AP-HP, Hôpital Necker, PICU, Paris, France (S.R.); Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), Paris, France (B.C.).
Valerie
V
Besson
From the PROTECT, INSERM, University Paris Diderot, France (P.-L.L., J.P., V.B., O.B., C.C.-M.); UPMC, AP-HP, Hôpital Armand Trousseau, PICU, Paris, France (P.-L.L.); Pharmacologie de la Circulation Cérébrale-EA4475, University Paris Descartes, Faculté de Pharmacie, France (V.B., B.P.); University Rene Descartes, AP-HP, Hôpital Necker, PICU, Paris, France (S.R.); Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), Paris, France (B.C.).
Bruno
B
Palmier
From the PROTECT, INSERM, University Paris Diderot, France (P.-L.L., J.P., V.B., O.B., C.C.-M.); UPMC, AP-HP, Hôpital Armand Trousseau, PICU, Paris, France (P.-L.L.); Pharmacologie de la Circulation Cérébrale-EA4475, University Paris Descartes, Faculté de Pharmacie, France (V.B., B.P.); University Rene Descartes, AP-HP, Hôpital Necker, PICU, Paris, France (S.R.); Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), Paris, France (B.C.).
Sylvain
S
Renolleau
From the PROTECT, INSERM, University Paris Diderot, France (P.-L.L., J.P., V.B., O.B., C.C.-M.); UPMC, AP-HP, Hôpital Armand Trousseau, PICU, Paris, France (P.-L.L.); Pharmacologie de la Circulation Cérébrale-EA4475, University Paris Descartes, Faculté de Pharmacie, France (V.B., B.P.); University Rene Descartes, AP-HP, Hôpital Necker, PICU, Paris, France (S.R.); Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), Paris, France (B.C.).
Olivier
O
Baud
From the PROTECT, INSERM, University Paris Diderot, France (P.-L.L., J.P., V.B., O.B., C.C.-M.); UPMC, AP-HP, Hôpital Armand Trousseau, PICU, Paris, France (P.-L.L.); Pharmacologie de la Circulation Cérébrale-EA4475, University Paris Descartes, Faculté de Pharmacie, France (V.B., B.P.); University Rene Descartes, AP-HP, Hôpital Necker, PICU, Paris, France (S.R.); Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), Paris, France (B.C.).
Bruno
B
Cauli
From the PROTECT, INSERM, University Paris Diderot, France (P.-L.L., J.P., V.B., O.B., C.C.-M.); UPMC, AP-HP, Hôpital Armand Trousseau, PICU, Paris, France (P.-L.L.); Pharmacologie de la Circulation Cérébrale-EA4475, University Paris Descartes, Faculté de Pharmacie, France (V.B., B.P.); University Rene Descartes, AP-HP, Hôpital Necker, PICU, Paris, France (S.R.); Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), Paris, France (B.C.). christiane.marlangue@gmail.com.
Christiane
C
Charriaut-Marlangue
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism*; D000818:Animals; D002560:Cerebrovascular Circulation; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D008833:Microcirculation; D000071876:Prostaglandin-E Synthases / Q000378:metabolism*; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism*
D052246:Cyclooxygenase 2 Inhibitors; D015121:6-Ketoprostaglandin F1 alpha; D051546:Cyclooxygenase 2; D000071876:Prostaglandin-E Synthases
COX-2; ischemia–reperfusion; microcirculation; prostaglandins; stroke