Prostaglandin D2 protects neonatal mouse brain from hypoxic ischemic injury.
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.
Taniguchi
Hidetoshi
H
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Mohri
Ikuko
I
Okabe-Arahori
Hitomi
H
Aritake
Kosuke
K
Wada
Kazuko
K
Kanekiyo
Takahisa
T
Narumiya
Shuh
S
Nakayama
Masahiro
M
Ozono
Keiichi
K
Urade
Yoshihiro
Y
Taniike
Masako
M
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000098:blood supply / Q000473:pathology; D001929:Brain Edema / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation
D018696:Neuroprotective Agents; D015230:Prostaglandin D2