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

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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.