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The Journal of Neuroscience, April 18, 2007, 27(16):4303-4312; doi:10.1523/JNEUROSCI.0321-07.2007
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Cellular/Molecular
Prostaglandin D2 Protects Neonatal Mouse Brain from Hypoxic Ischemic Injury
Hidetoshi Taniguchi,1 Ikuko Mohri,1,2 Hitomi Okabe-Arahori,1 Kosuke Aritake,3 Kazuko Wada,1 Takahisa Kanekiyo,1 Shuh Narumiya,4 Masahiro Nakayama,5 Keiichi Ozono,1 Yoshihiro Urade,3 andMasako Taniike1,2 1Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan, 2Department of Mental Health and Environmental Effects Research, The Research Center for Child Mental Development, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan, 3Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan, 4Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan, and 5Division of Clinical Laboratory Medicine and Anatomic Pathology, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan
Correspondence should be addressed to Dr. Masako Taniike, Department of Mental Health and Environmental Effects Research, The Research Center for Child Mental Development, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. Email: masako{at}ped.med.osaka-u.ac.jp
Prostaglandin D2 (PGD) is synthesized by hematopoietic PGD synthase (HPGDS) or lipocalin-type PGDS (L-PGDS), depending on the organ in which it is produced, and binds specifically to either DP1 or DP2 receptors. We investigated the role of PGD2 in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonatal mice at postnatal day 7. In wild-type mice, hypoxia-ischemia increased PGD2 production in the brain up to 90-fold compared with the level in sham-operated brains at 10 min after cessation of hypoxia. Whereas the size of the infarct was not changed in L-PGDS or DP2 knock-out mouse brains compared with that in the wild-type HIE brains, it was significantly increased in HPGDS–L-PGDS double knock-out or DP1 knock-out mice. The PGD2 level in L-PGDS, HPGDS, and HPGDS–L-PGDS knock-out mice at 10 min of reoxygenation was 46, 7, and 1%, respectively, of that in the wild-type ones, indicating the infarct size to be in inverse relation to the amount of PGD2 production. DP1 receptors were exclusively expressed in endothelial cells after 1 h of reoxygenation, and cerebral blood flow decreased more rapidly after the onset of hypoxia and did not return to the baseline level after reoxygenation in HPGDS–L-PGDS knock-out mice. Endothelial cells were severely damaged in HPGDS–L-PGDS and DP1 knock-out mice after 1 h of reoxygenation. In the human neonatal HIE brain, HPGDS-positive microglia were increased in number. In conclusion, it is probable that PGD2 protected the neonatal brain from hypoxic-ischemic injury mainly via DP1 receptors by preventing endothelial cell degeneration.
Key words: hypoxic-ischemic encephalopathy; prostaglandin D2; hematopoietic PGD synthase; lipocalin-type PGD synthase; DP1 receptor; microangiopathy
Received July 31, 2006; revised March 6, 2007; accepted March 12, 2007.
Correspondence should be addressed to Dr. Masako Taniike, Department of Mental Health and Environmental Effects Research, The Research Center for Child Mental Development, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. Email: masako{at}ped.med.osaka-u.ac.jp
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