Early induction of neuronal lipocalin-type prostaglandin D synthase after hypoxic-ischemic injury in developing brains.
Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is up-regulated in oligodendrocytes (OLs) in mouse models for genetic neurological disorders including globoid cell leukodystrophy (twitcher) and GM1 and GM2 gangliosidoses and in the brain of patients with multiple sclerosis. Since L-PGDS-deficient twitcher mice undergo extensive neuronal death, we concluded that L-PGDS functions protectively against neuronal degeneration. In this study, we investigated whether L-PGDS is also up-regulated in acute and massive brain injury resulting from neonatal hypoxic-ischemic encephalopathy (HIE). Analysis of brains from human neonates who had died from HIE disclosed that the surviving neurons in the infarcted lesions expressed L-PGDS. Mouse models for neonatal HIE were made on postnatal day (PND) 7. Global infarction in the ipsilateral hemisphere was evident at 24h after reoxygenation in this model. Intense L-PGDS immunoreactivity was already observed at 10 min after reoxygenation in apparently normal neurons in the cortex, and thereafter, in neurons adjacent to the infarcted area. Quantitative RT-PCR revealed that the L-PGDS mRNA level of the infarcted hemisphere was 33-fold higher than that of the sham-operated mouse brains at 1h after reoxygenation and that it decreased to the normal level by 24h thereafter. Furthermore, in both human and mouse brains, many of L-PGDS-positive cells were also immunoreactive for p53; and some of these expressed cleaved caspase-3. The expression of L-PGDS in degenerating neurons implies that L-PGDS functions as an early stress protein to protect against neuronal death in the HIE brain.
Taniguchi
Hidetoshi
H
Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan.
Mohri
Ikuko
I
Okabe-Arahori
Hitomi
H
Kanekiyo
Takahisa
T
Kagitani-Shimono
Kuriko
K
Wada
Kazuko
K
Urade
Yoshihiro
Y
Nakayama
Masahiro
M
Ozono
Keiichi
K
Taniike
Masako
M
D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000201:enzymology* / Q000254:growth & development*; D053148:Caspase 3 / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology*; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis*; D054834:Lipocalins / Q000096:biosynthesis*; D051379:Mice; D009474:Neurons / Q000201:enzymology*; D009836:Oligodendroglia / Q000201:enzymology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016707:Tissue Fixation; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D000911:Antibodies, Monoclonal; D054834:Lipocalins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D053148:Caspase 3; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase