慢性间歇性低氧通过钙超载激活内质网应激诱导海马神经元凋亡

doi:10.3969/j.issn.1006-5725.2025.23.005

摘要/Abstract

摘要：

目的探讨慢性间歇性低氧（CIH）对大鼠海马神经元的损伤作用及其与内质网（ER）应激相关凋亡通路的关系。方法将雄性SD大鼠随机分为对照组和CIH组，每组各8只。CIH组大鼠每天暴露于间歇性低氧环境8 h，持续8周。采用HE染色与透射电镜观察海马组织神经元形态学变化；TUNEL法检测神经元凋亡；流式细胞术测定胞内Ca2?水平；qPCR与Western blot检测GRP78、CHOP和Caspase-3的mRNA及蛋白表达。结果与对照组相比，CIH组大鼠海马神经元出现明显形态学损伤，包括细胞排列紊乱、胞浆溶解及粗面内质网肿胀；TUNEL检测显示凋亡细胞数显著增加（P < 0.05）；流式检测提示胞内Ca2?水平升高（P < 0.05）；GRP78、CHOP和Caspase-3的mRNA及蛋白水平均明显上调（P < 0.05）。结论 CIH可导致大鼠海马神经元显著损伤和凋亡，其机制与Ca2?稳态紊乱介导的ER应激及下游凋亡通路激活密切相关。

关键词: 慢性间歇性低氧, 钙超载, 内质网应激, 细胞凋亡

Abstract:

Objective To investigate the effects of chronic intermittent hypoxia （CIH） on hippocampal neuronal injury in rats， and to clarify the role of endoplasmic reticulum （ER） stress?related apoptotic pathways. Methods Male Sprague?Dawley rats were randomly assigned to a control group （n = 8） or a CIH group （n = 8）. The CIH group was exposed to intermittent hypoxia for 8 h/day over 8 weeks. Hippocampal neuronal morphology was examined by hematoxylin?eosin staining and transmission electron microscopy. Neuronal apoptosis was assessed using the TUNEL assay. Intracellular Ca2? levels were measured by flow cytometry. The mRNA and protein expression of ER stress?related factors （GRP78， CHOP） and the apoptotic effector Caspase-3 were quantified by qPCR and Western blot. Results Compared with controls， rats in the CIH group exhibited marked hippocampal neuronal damage， including disrupted cytoarchitecture， cytoplasmic dissolution， and swollen rough ER. Ultrastructural analysis revealed nuclear deformation and organelle disruption. TUNEL assay demonstrated a significant increase in apoptotic cells （P < 0.05）. Flow cytometry showed elevated intracellular Ca2? levels （P < 0.05）. GRP78， CHOP， and Caspase-3 were significantly upregulated at both mRNA and protein levels in the CIH group （all P < 0.05）. Conclusion CIH induces pronounced hippocampal neuronal injury and apoptosis in rats， associated with Ca2? dysregulation and activation of ER stress?mediated apoptotic pathways. These findings provide experimental evidence for elucidating the mechanisms of OSAHS-related neuronal injury and identifying potential therapeutic targets.

Key words: chronic intermittent hypoxia, calcium overload, endoplasmic reticulum stress, apoptosis

中图分类号:

R592

李瑜,陈玉岚,连思念,王红. 慢性间歇性低氧通过钙超载激活内质网应激诱导海马神经元凋亡[J]. 实用医学杂志, 2025, 41(23): 3659-3665.

Yu LI,Yulan CHEN,Sinian LIAN,Hong. WANG. Chronic intermittent hypoxia induces hippocampal neuronal apoptosis by activating endoplasmic reticulum stress via calcium overload[J]. The Journal of Practical Medicine, 2025, 41(23): 3659-3665.

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指标	对照组	CIH	t值	P值
GRP78	0.583 ± 0.035	0.725 ± 0.055	-4.341	0.005
CHOP	0.313 ± 0.031	0.469 ± 0.048	-5.489	0.002
caspase-3	0.315 ± 0.067	0.672 ± 0.096	-6.083	0.001