Hypoxia-ischemic insult in neonatal rats induced slowly progressive brain damage related to memory impairment and its development of new drugs.

本研究旨在探讨缺氧缺血性脑损伤与八臂迷宫空间学习障碍的关系。我们首先确定HI后2、5、9和17周恢复后的病理结果。结果表明，脑损伤从恢复2周到恢复17周。为了阐明脑损伤变化的时间过程，我们用磁共振成像（MRI）研究了同一个体在HI后恢复5周、9周和57周后的组织学变化。MRI表现与组织学改变相似，恢复57周后对侧半球脑损害加重。为了研究脑功能的变化是否与MRI和组织学变化相关，分别在恢复7周或16周时进行了8臂径向迷宫。恢复16周时开始的8臂径向迷宫空间学习障碍较恢复7周时严重，表明空间学习障碍是进行性的，并依赖于脑损伤的程度。本研究的结果是第一次证明，这些进化和特定的脑损伤后，HI是缓慢和进行性加重到对侧半球和HI是在显示出迟发性脑功能障碍的风险。此外，植入封装的胶质细胞系源性神经营养因子（GDNF）分泌细胞不仅有效地减少脑损伤，而且还抑制大鼠HI后的学习和记忆障碍，这表明HI诱导的脑损伤与GDNF减少有关。

The present study was designed to determine potential associations between the brain damage induced by hypoxic-ischemie (HI) insult and spatial learning impairment in 8-arm radial maze task. We first determined the pathological outcomes after 2, 5, 9 and 17 weeks of recovery following the HI. The results show that the brain damage was progressed from 2 weeks of recovery and up to 17 weeks of recovery. To clarify the time course of the brain damage changes, we investigated the histological changes of the same individual with magnetic resonance imaging (MRI) after 5, 9 and 57 weeks of recovery following the HI. The 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. To investigate whether alteration in brain function was correlated with MRI and histological changes, the 8-arm radial maze was performed at 7 weeks or 16 weeks of recovery, respectively. 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. The results of the present study are the first demonstration that these evolutional and specific brain damage following the HI is slowly and progressively exacerbated to the contralateral hemisphere and the HI are at risk for showing a late impairment of brain function. Moreover, the implantation of encapsulated glial cell line-derived neurotrophic factor (GDNF)-secreting cells was effective in not only reducing brain damage but also inhibiting learning and memory impairment following, HI in rats, suggesting that the HI-induced brain damage is related to GDNF reduction.