Taniguchi Hidetoshi, Mohri Ikuko, Okabe-Arahori Hitomi, Kanekiyo Takahisa, Kagitani-Shimono Kuriko, Wada Kazuko, Urade Yoshihiro, Nakayama Masahiro, Ozono Keiichi, Taniike Masako
Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan.
Neurosci Lett. 2007 Jun 8;420(1):39-44. doi: 10.1016/j.neulet.2007.04.016. Epub 2007 Apr 11.
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.
脂联素型前列腺素（PG）D合成酶（L-PGDS）在包括球状细胞脑白质营养不良（震颤小鼠）、GM1和GM2神经节苷脂病等遗传性神经疾病的小鼠模型的少突胶质细胞（OLs）中以及多发性硬化症患者的大脑中上调。由于L-PGDS缺陷的震颤小鼠会发生广泛的神经元死亡，我们得出结论，L-PGDS具有保护神经元免于退化的功能。在本研究中，我们调查了L-PGDS在新生儿缺氧缺血性脑病（HIE）导致的急性大面积脑损伤中是否也会上调。对死于HIE的人类新生儿大脑进行分析发现，梗死灶中存活的神经元表达L-PGDS。在出生后第7天（PND7）建立新生儿HIE小鼠模型。在该模型中，复氧24小时后同侧半球出现全脑梗死。复氧10分钟后，在皮质中看似正常的神经元中已观察到强烈的L-PGDS免疫反应性，此后，在梗死区域附近的神经元中也观察到。定量逆转录聚合酶链反应（RT-PCR）显示，复氧后lh梗死半球的L-PGDS mRNA水平比假手术小鼠脑高33倍，此后24小时降至正常水平。此外，在人类和小鼠大脑中，许多L-PGDS阳性细胞也对p53呈免疫反应；其中一些表达裂解的半胱天冬酶-3。L-PGDS在退化神经元中的表达表明，L-PGDS作为一种早期应激蛋白，在HIE脑内发挥保护神经元免于死亡的作用。
