Department and Institute of Physical Therapy and Assistive Technology, National Yang-Ming University, Taipei, Taiwan.
PLoS One. 2011;6(8):e24001. doi: 10.1371/journal.pone.0024001. Epub 2011 Aug 24.
Memory impairment is a frequent complication of brain ischemia. Neurogenesis is implicated in learning and memory and is regulated by the transcription factor c-Fos. Preconditioning intermittent hypoxia (IH) attenuates ischemia-related memory impairments, but it is not known whether post-ischemia IH intervention has a similar effect. We investigated the effects of post-ischemia IH on hippocampal neurogenesis and c-Fos expression as well as spatial learning and memory in rats.
METHODOLOGY/PRINCIPAL FINDINGS: Focal cerebral ischemia was induced in some rats by middle cerebral artery occlusion (MCAO), while other rats received sham MCAO surgery. Beginning a week later, half of the rats of each group received IH interventions (12% oxygen concentration, 4 hrs/d, for 7 d) and half received sham IH sessions. An additional group of rats received MCAO, IH, and injections of the neurogenesis-impairing agent 3'-AZT. Spatial learning and memory was measured in the Morris water maze, and hippocampal neurogenesis and c-Fos expression were examined. Hypoxia-inducible factor 1α (HIF-1α) and phosphorylated mitogen-activated protein kinase (pMAPK) were considered as possible mediators of IH-induced changes in neurogenesis and c-Fos expression. IH intervention following MCAO resulted in recovered spatial memory, increased hippocampal neurogenesis, and increased expression of c-Fos in newborn hippocampal cells. These effects were blocked by 3'-AZT. IH intervention following MCAO also was associated with increased hippocampal pMAPK and HIF-1α expression.
CONCLUSIONS/SIGNIFICANCE: IH intervention following MCAO rescued ischemia-induced spatial learning and memory impairments, likely by inducing hippocampal neurogenesis and c-Fos expression through mediators including pMAPK and HIF-1α.
记忆损伤是脑缺血的常见并发症。神经发生与学习和记忆有关，受转录因子 c-Fos 调节。预处理间歇性低氧（IH）可减轻与缺血相关的记忆损伤，但尚不清楚缺血后 IH 干预是否具有类似的效果。我们研究了缺血后 IH 对大鼠海马神经发生和 c-Fos 表达以及空间学习和记忆的影响。
方法/主要发现：一些大鼠通过大脑中动脉闭塞（MCAO）诱导局灶性脑缺血，而其他大鼠接受假 MCAO 手术。一周后，每组大鼠的一半接受 IH 干预（12%氧气浓度，4 小时/天，共 7 天），另一半接受假 IH 干预。另一组大鼠接受 MCAO、IH 和神经发生损伤剂 3'-AZT 注射。在 Morris 水迷宫中测量空间学习和记忆，检查海马神经发生和 c-Fos 表达。缺氧诱导因子 1α（HIF-1α）和磷酸化丝裂原激活蛋白激酶（pMAPK）被认为是 IH 诱导神经发生和 c-Fos 表达变化的可能介质。MCAO 后 IH 干预导致空间记忆恢复，海马神经发生增加，新生海马细胞中 c-Fos 表达增加。这些作用被 3'-AZT 阻断。MCAO 后 IH 干预还与海马 pMAPK 和 HIF-1α 表达增加相关。
结论/意义：MCAO 后 IH 干预挽救了缺血引起的空间学习和记忆损伤，可能通过包括 pMAPK 和 HIF-1α 在内的介质诱导海马神经发生和 c-Fos 表达。
