Department of Pathology and Pathophysiology, School of Basic Medical Science, Kunming Medical University, Kunming, 650500, China.
Neurosci Bull. 2016 Feb;32(1):99-107. doi: 10.1007/s12264-015-0003-8. Epub 2016 Jan 15.
Our previous study together with other investigations have reported that neonatal hypoxia or ischemia induces long-term cognitive impairment, at least in part through brain inflammation and hypomyelination. However, the detailed mechanisms are not fully understood. Here, we used a rodent model of neonatal hypoxia by subjecting postnatal day 0 (P0) rat pups to systemic hypoxia (3.5 h). We found that neonatal hypoxia increased the glutamate content and initiated inflammatory responses at 4 h and 1 day after hypoxia, caused hypomyelination in the corpus callosum, and impaired hippocampus-dependent learning and memory when assessed 30-60 days after hypoxia. Interestingly, much of the hypoxia-induced brain damage was ameliorated by treatment with the ATP analogue 2',3'-0-(2,4,6-trinitrophenyl)-adenosine 5'-triphosphate (TNP-ATP; blocks all ionotropic P2X1-7 receptors), whereas treatment with pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; inhibits P2X1-3 and P2X5-7 receptors) was less neuroprotective. Our data indicated that activation of ionotropic ATP receptors might be partially, if not fully, involved in glutamate deregulation, neuroinflammation, hypomyelination, and cognitive dysfunction after neonatal hypoxia.
我们之前的研究以及其他研究已经表明，新生儿缺氧或缺血会导致长期认知障碍，至少部分是通过脑炎症和少突胶质细胞发育不良引起的。然而，其详细机制尚不完全清楚。在这里，我们通过对出生后 0 天（P0）的幼鼠进行全身缺氧（3.5 h）建立了新生儿缺氧的啮齿动物模型。我们发现，新生儿缺氧会在缺氧后 4 小时和 1 天增加谷氨酸含量并引发炎症反应，导致胼胝体脱髓鞘，并在缺氧后 30-60 天评估时损害海马依赖性学习和记忆。有趣的是，用三磷酸腺苷类似物 2',3'-O-(2,4,6-三硝基苯)-腺苷 5'-三磷酸（TNP-ATP；阻断所有离子型 P2X1-7 受体）治疗可减轻大部分缺氧引起的脑损伤，而用吡哆醛 6-偶氮苯-2',4'-二磺酸（PPADS；抑制 P2X1-3 和 P2X5-7 受体）治疗的神经保护作用则较小。我们的数据表明，离子型 ATP 受体的激活可能部分（如果不是完全）参与了新生儿缺氧后谷氨酸失调、神经炎症、少突胶质细胞发育不良和认知功能障碍。
