Prostaglandin D sub(2) Protects Neonatal Mouse Brain from Hypoxic Ischemic Injury

• Published in: The Journal of neuroscience 2007-04, Vol.27 (16), p.4303-4312
• Main Authors: Taniguchi, Hidetoshi, Mohri, Ikuko, Okabe-Arahori, Hitomi, Aritake, Kosuke, Wada, Kazuko, Kanekiyo, Takahisa, Narumiya, Shuh, Nakayama, Masahiro, Ozono, Keiichi, Urade, Yoshihiro, Taniike, Masako
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401

Prostaglandin D sub(2) (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 DP sub(1) or DP sub(2) receptors. We investigated the role of PGD sub(2) in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonatal mice at postnatal day 7. In wild-type mice, hypoxia-ischemia increased PGD sub(2) 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 DP sub(2) 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 DP sub(1) knock-out mice. The PGD sub(2) 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 PGD sub(2) production. DP sub(1) 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 DP sub(1) 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 PGD sub(2) protected the neonatal brain from hypoxic-ischemic injury mainly via DP sub(1) receptors by preventing endothelial cell degeneration.