Department of Critical Care and Emergency, Guangdong Provincial People' Hospital , Guangdong Academy of Medical Sciences , Guangzhou 510080 , China.
Jieyang People's Hospital, Jieyang Affiliated Hospital , Sun Yat-sen University , Jieyang 522000 , China.
ACS Chem Neurosci. 2019 May 15;10(5):2560-2575. doi: 10.1021/acschemneuro.9b00051. Epub 2019 Mar 20.
Infectious exposure during the perinatal period may predispose to permanent neurological disorders in later life. Here we investigated whether changes in interleukin-1β (IL-1β) are associated with cognitive dysfunction in later life of septic neonatal rats through suppression of neurogenesis in the hippocampus. Sprague-Dawley rats (1-day old) administered lipopolysaccharide (LPS) showed upregulated expression of IL-1β and IL-1 receptors in the hippocampus. At 28 days of age, rats showed longer escape latencies and decreased numbers of crossings after LPS administration. This was coupled with increased numbers of glial fibrillary acidic protein positive (GFAP) astrocytes and decreased numbers of neuronal nuclei positive (NeuN) cells. The numbers of sex-determining region Y-box 2 positive (SOX2) and doublecortin positive (DCX) cells were decreased at 1 and 3 days but was increased at 7 and 14 days. The proliferation of SOX2 cells was inhibited at 1 and 3 days but increased at 7 and 14 days. In vitro IL-1β administration suppressed the proliferation of neural progenitor cells (NPCs) in neurospheres derived from the hippocampus. GFAP expression was upregulated in differentiated NPCs treated with IL-1β for 4 days, but expression of DCX and microtubule associated protein-2 (MAP2) was decreased. Remarkably, the Notch signaling pathway involved in antineurogenic and progliogenic differentiation of NPCs was activated after IL-1β administration. The results show that following LPS injection in neonatal rats, microglia were activated and generated excess amounts of IL-1β in the hippocampus. It is suggested that this might have contributed to inhibiting neurogenesis but promoting gliogenesis of NPCs via activation of the Notch signaling pathway and maybe one of the causes for cognitive dysfunction in septic neonatal rats in later life.
围产期的感染暴露可能使新生儿在以后的生活中易患永久性神经障碍。在这里，我们通过抑制海马体中的神经发生来研究内毒素-1β（IL-1β）的变化是否与败血症新生大鼠以后的生活中的认知功能障碍有关。给予脂多糖（LPS）的斯普拉格-道利大鼠（1 天大）在海马体中表现出 IL-1β和 IL-1 受体的上调表达。在 28 天时，大鼠在 LPS 给药后表现出更长的逃避潜伏期和减少的穿越次数。这伴随着胶质纤维酸性蛋白阳性（GFAP）星形胶质细胞数量的增加和神经元核阳性（NeuN）细胞数量的减少。性别决定区 Y 框 2 阳性（SOX2）和双皮质素阳性（DCX）细胞的数量在 1 天和 3 天减少，但在 7 天和 14 天增加。SOX2 细胞的增殖在 1 天和 3 天受到抑制，但在 7 天和 14 天增加。体外 IL-1β 给药抑制了来源于海马体的神经球衍生的神经祖细胞（NPC）的增殖。用 IL-1β 处理 4 天的分化 NPC 中 GFAP 表达上调，但 DCX 和微管相关蛋白-2（MAP2）表达减少。值得注意的是，在给予 IL-1β 后，NPC 中的 Notch 信号通路被激活，该信号通路涉及 NPC 的抗神经发生和促神经发生分化。结果表明，在新生大鼠注射 LPS 后，小胶质细胞被激活并在海马体中产生过量的 IL-1β。这表明，这可能通过激活 Notch 信号通路抑制 NPC 的神经发生但促进 NPC 的神经胶质发生，这可能是败血症新生大鼠以后的生活中认知功能障碍的原因之一。
