Zhang Kai, Ma Dandi, Song Ruobing, Wu Yunxiao, Xu Zhifei, Ni Xin
Clinical Department of National Clinical Research Center for Respiratory Diseases, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.
Department of Otolaryngology, Head and Neck Surgery, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.
Mol Neurobiol. 2025 May 7. doi: 10.1007/s12035-025-05018-w.
Obstructive sleep apnea syndrome (OSA), characterized by chronic intermittent hypoxia (CIH), is linked to cognitive impairment and neuronal damage. Leptin, a peptide hormone involved in energy metabolism, has shown neuroprotective effects in various neurological disorders, yet its role in CIH-induced cognitive impairment remains unclear. This study used a CIH mouse model to investigate the effects of leptin on cognitive function and neuronal damage, with a particular focus on Sirtuin 1 (SIRT1) as a potential molecular mediator. Mice were exposed to CIH and treated with leptin, with or without a SIRT1 inhibitor. Cognitive performance was assessed using the Morris Water Maze (MWM) and Y-maze tests. Neuronal damage was evaluated by H&E and Nissl staining, while oxidative stress was measured by Reactive Oxygen Species (ROS) and malondialdehyde (MDA) levels, and Superoxide Dismutase (SOD) activity. SIRT1 expression was determined via western blot analysis. Leptin treatment significantly improved cognitive performance in CIH mice, evidenced by reduced escape latency, increased platform crossings in the MWM, and enhanced alternation rates in the Y-maze. Additionally, leptin mitigated CIH-induced neuronal damage and oxidative stress, demonstrated by improved neuronal structure and reduced ROS and MDA levels. These benefits were associated with increased SIRT1 expression, whereas SIRT1 inhibition reversed leptin's positive effects, highlighting the crucial role of SIRT1 in mediating leptin's neuroprotective effects. These findings suggest that leptin alleviates CIH-induced cognitive dysfunction and neuronal damage through SIRT1 upregulation, offering insights into potential therapeutic mechanisms and future clinical applications.
阻塞性睡眠呼吸暂停综合征（OSA）以慢性间歇性缺氧（CIH）为特征，与认知障碍和神经元损伤有关。瘦素是一种参与能量代谢的肽类激素，已在多种神经疾病中显示出神经保护作用，但其在CIH诱导的认知障碍中的作用仍不清楚。本研究使用CIH小鼠模型来研究瘦素对认知功能和神经元损伤的影响，特别关注沉默调节蛋白1（SIRT1）作为潜在的分子介质。将小鼠暴露于CIH并给予瘦素治疗，同时给予或不给予SIRT1抑制剂。使用莫里斯水迷宫（MWM）和Y迷宫试验评估认知表现。通过苏木精和伊红（H&E）染色和尼氏染色评估神经元损伤，同时通过活性氧（ROS）和丙二醛（MDA）水平以及超氧化物歧化酶（SOD）活性测量氧化应激。通过蛋白质印迹分析确定SIRT1表达。瘦素治疗显著改善了CIH小鼠的认知表现，表现为逃避潜伏期缩短、MWM中平台穿越次数增加以及Y迷宫中交替率提高。此外，瘦素减轻了CIH诱导的神经元损伤和氧化应激，表现为神经元结构改善以及ROS和MDA水平降低。这些益处与SIRT1表达增加有关，而SIRT1抑制则逆转了瘦素的积极作用，突出了SIRT1在介导瘦素神经保护作用中的关键作用。这些发现表明，瘦素通过上调SIRT1减轻CIH诱导的认知功能障碍和神经元损伤，为潜在的治疗机制和未来的临床应用提供了见解。
