Investigation of cerebral paralysis and its development of new drugs in neonatal hypoxic-ischemia-induced slowly progressive brain damage

本研究旨在探讨8臂放射状迷宫作业中缺氧缺血性脑损伤与空间学习障碍之间的关系。脑损伤从2周恢复到17周恢复。磁共振成像(MRI)改变与组织学改变相似，在HI后57周恢复时，对侧大脑半球的损害加重。8臂放射状迷宫恢复16周时的空间学习障碍较恢复7周时更为严重，说明空间学习障碍是进行性的，并与脑损伤程度有关。因此，我们将这种现象称为缓慢进行性脑损伤(sPbD，Nuerosi Lett，376,194-199,2005)。1)脑缺血后2周起丘脑和下丘脑星形胶质细胞逐渐增多，9周后下丘脑GFAP阳性细胞逐渐增多。2)脑脊液中谷氨酸、氮氧化物和皮质酮含量的时程：谷氨酸在缺氧缺血后2~17周下降，一氧化氮从缺氧缺血后9周开始升高。3)HI后17周脑脊液对正常大鼠CRT任务的影响，HI后17周校正脑脊液，静脉注射。在完好无损的老鼠身上。脑脊液(20~40ul)对CRT任务无明显影响，提示sPbD与激活下丘脑星形胶质细胞、减少谷氨酸和增加NOx有关。

The present study was designed to determine potential associations between the brain damage induced by hypoxic-ischemic (HI) insult and spatial learning impairment in 8-arm radial maze task. The brain damage was progressed from 2 weeks of recovery and up to 17 weeks of recovery. The magnetic resonance imaging (MRI) changes were similar with the histological changes, and the brain damages were exacerbated in contralateral hemisphere after 57 weeks of recovery following the HI. The spatial learning impairments of 8-arm radial maze starting at 16 weeks of recovery were more severe than those at 7 weeks of recovery, indicating that the spatial learning impairments were progressive and depended on the degree of brain damage. Therefore we called this phenomenon, slowly progressive brain damage (SPBD, Nuerosci Lett, 376,194-199,2005). We examined this mechanism of the SPBD.1) The time course of astrocyte in thalamus and hypothalamus The GFAP-positive cell progressively increased in the thalamus from 2 weeks and in the hypothalamus from 9 weeks after the HI. The S-100 protein-positive cells were observed in both thalamus and hypothalamus 17 weeks after the HI.2) The time course of glutamate, NOx and corticosterone in the CSF The glutamate decreased from 2 weeks to 17 weeks after the HI, and the NOx increased from 9 weeks after the HI. The corticosterone tended to decrease in the female rats.3) Effect of the CSF at 17 weeks after the HI on the CRT task in intact rats.The CSF was corrected at 17 weeks after the HI and was injected i.c.v. in intact rats. The CSF (20-40 uL) did not affect the CRT task.These results suggest that the SPBD was related to the activating of astrocyte in the hypothalamus, a decrease in the glutamate and an increase in the NOx.