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

本研究旨在确定8臂径向迷宫任务中缺氧缺血性脑损伤与空间学习障碍之间的潜在联系。脑损伤的进展从恢复2周到恢复17周。磁共振成像（MRI）变化与组织学变化相似，HI术后恢复57周后对侧半球脑损伤加重。8臂径向迷宫的空间学习障碍在恢复16周时比恢复7周时更为严重，表明空间学习障碍是进行性的，与脑损伤程度有关。因此，我们称这种现象为缓慢进行性脑损伤（SPBD，神经科学通报，376,194-199,2005）。1)丘脑和下丘脑星形胶质细胞的时间过程：在HI后2周，丘脑中gfap阳性细胞逐渐增加，下丘脑中gfap阳性细胞从9周开始逐渐增加。HI后17周丘脑和下丘脑均可见S-100蛋白阳性细胞。2)脑脊液中谷氨酸、氮氧化物和皮质酮的时间过程：HI后2 ~ 17周谷氨酸降低，HI后9周氮氧化物升高。雌性大鼠的皮质酮有降低的趋势。3) HI后17周脑脊液对正常大鼠CRT任务的影响。在HI后17周校正脑脊液，并在完整大鼠中注射体外循环。CSF （20 ~ 40ul）对CRT任务无影响。上述结果提示SPBD与下丘脑星形胶质细胞的激活、谷氨酸的减少和氮氧化物的增加有关。

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.