间歇性缺氧大鼠模型中听觉皮层损伤机制及复氧的保护作用

文献信息

中文摘要

背景： 与阻塞性睡眠呼吸暂停相关的间歇性缺氧可损害听觉功能，但听觉皮层损伤的早期机制以及恢复正常氧合后这些变化恢复的程度仍不清楚。本研究探讨了间歇性缺氧大鼠模型中听觉皮层损伤的机制，并评估了复氧的保护作用。方法：成年雄性Sprague-Dawley大鼠被分配到对照组、间歇性缺氧组、间歇性缺氧后常氧恢复1周组，或对照组后常氧恢复组。结果：短期间歇性缺氧导致高频听力损失并增加初级听觉皮层中的自发放电。常氧恢复1周后，听阈和皮层放电率恢复至与对照组相当的水平。谷氨酸水平在各组间无显著差异，而γ-氨基丁酸和5-羟色胺水平在间歇性缺氧后常氧恢复组中升高。间歇性缺氧增加超氧化物歧化酶活性，降低过氧化氢酶活性，并升高肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6的水平。常氧恢复使过氧化氢酶活性正常化并降低肿瘤坏死因子-α和白细胞介素-6水平，而超氧化物歧化酶活性和白细胞介素-1β水平仍保持升高。代谢组学分析发现不饱和脂肪酸生物合成、支链氨基酸代谢、铁死亡相关通路、氧化还原相关代谢以及氨基酸和蛋白质周转的改变，其中若干改变在恢复后持续存在。结论：这些发现表明，急性间歇性缺氧诱导的听觉功能障碍和皮层过度兴奋是可逆的，而氧化还原、炎症和代谢异常则异步恢复。功能恢复后持续存在的分子紊乱可能为进一步研究阻塞性睡眠呼吸暂停相关中枢听觉损伤提供潜在靶点。

英文摘要

Intermittent hypoxia associated with obstructive sleep apnea can impair auditory function, but the early mechanisms underlying auditory cortical injury and the extent to which these changes recover after the restoration of normoxia remain unclear. This study investigated the mechanisms underlying auditory cortical injury in a rat model of intermittent hypoxia and evaluated the protective effects of reoxygenation. Adult male Sprague-Dawley rats were assigned to control, intermittent hypoxia, intermittent hypoxia followed by 1 week of normoxic recovery, or control followed by normoxic recovery groups. Short-term intermittent hypoxia caused high-frequency hearing loss and increased spontaneous firing in the primary auditory cortex. After 1 week of normoxic recovery, auditory thresholds and cortical firing rates returned to levels comparable to those in the control group. Glutamate levels did not differ significantly among the groups, whereas γ-aminobutyric acid and 5-hydroxytryptamine levels were elevated in the intermittent hypoxia followed by normoxic recovery group. Intermittent hypoxia increased superoxide dismutase activity, reduced catalase activity, and elevated the levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6. Normoxic recovery normalized catalase activity and reduced tumor necrosis factor-α and interleukin-6 levels, whereas superoxide dismutase activity and interleukin- 1β levels remained elevated. Metabolomic analysis identified alterations in unsaturated fatty acid biosynthesis, branched-chain amino acid metabolism, ferroptosis-related pathways, redox-related metabolism, and amino acid and protein turnover, several of which persisted after recovery. These findings indicate that acute intermittent hypoxia-induced auditory dysfunction and cortical hyperexcitability are reversible, whereas redox, inflammatory, and metabolic abnormalities recover asynchronously. Persistent molecular disturbances after functional recovery may provide potential targets for further investigation of obstructive sleep apnea-associated central auditory injury.