This study explored the role of the p38 mitogen-activated protein kinase (MAPK) signaling pathway in hippocampal neuron autophagy in rats with chronic intermittent hypoxia (CIH). Sixty-four male Sprague-Dawley rats were randomly divided to normoxic control (CON), CIH (subdivided into groups A, B, and C undergoing intermittent hypoxia for 2, 4, and 6 weeks, respectively), solvent (CIH+Veh), or p38MAPK inhibitor (CIH+SB203580) groups. DMSO and SB203580 were injected intraperitoneally 30 min before hypoxia in CIH+Veh and CIH+SB203580 group rats, respectively. Rat learning and memory were evaluated via the Morris water maze test. Ultrastructural changes in the hippocampal CA1 region autophagic vesicles and neurons were observed under transmission electron and light microscopy. Hippocampal microtubule-associated proteins were detected by western blot. Morris water maze test showed that CIH+SB203580 group rats spent significantly more time on the platform quadrant and crossed the platform more times than CIH+Veh group rats (P < 0.01). HE staining showed greater rat cell damage in the CIH+SB group than in the CIH and CIH+Veh groups. Western blot analysis showed that CIH+SB group rats had significantly lower p-p38MAPK/p38MAPK, LC3I, and p62 expression and higher beclin-1 expression than CIH+Veh group rats (P < 0.01). Electron microscopy showed that CIH+SB203580 group rats had several small hippocampal neuron autophagic vesicles. On immunofluorescence analyses, it showed a higher LC3II expression in CIH+SB203580 group rats than in CIH+Veh group rats (P < 0.01). These results indicate that inhibition of the CIH p38MAPK signaling pathway can activate autophagy and protect hippocampal neurons in rats.

中文翻译：

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p38MAPK信号通路在慢性间歇性缺氧大鼠海马神经元自噬中的作用

本研究探讨了 p38 丝裂原活化蛋白激酶 (MAPK) 信号通路在慢性间歇性缺氧 (CIH) 大鼠海马神经元自噬中的作用。将 64 只雄性 Sprague-Dawley 大鼠随机分为常氧对照 (CON)、CIH（细分为 A、B 和 C 组，分别进行 2、4 和 6 周的间歇性缺氧）、溶剂 (CIH+Veh) ，或 p38MAPK 抑制剂 (CIH+SB203580) 组。DMSO和SB203580分别在CIH+Veh和CIH+SB203580组大鼠缺氧前30分钟腹腔注射。通过莫里斯水迷宫测试评估大鼠的学习和记忆。透射电镜和光镜下观察海马CA1区自噬小泡和神经元的超微结构变化。通过蛋白质印迹检测海马微管相关蛋白。Morris水迷宫试验表明，CIH+SB203580组大鼠在平台象限停留的时间明显长于CIH+Veh组大鼠，越过平台的次数显着高于CIH+Veh组（P < 0.01）。HE染色显示CIH+SB组大鼠细胞损伤大于CIH和CIH+Veh组。Western blot分析显示，CIH+SB组大鼠p-p38MAPK/p38MAPK、LC3I、p62表达明显低于CIH+Veh组大鼠，而beclin-1表达明显高于CIH+Veh组（P < 0.01）。电镜显示CIH+SB203580组大鼠海马神经元自噬小泡数个。免疫荧光分析显示，CIH+SB203580组大鼠LC3II表达高于CIH+Veh组大鼠（P < 0.01）。