Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, NO.277 Yanta West Road, Yanta District, Xi'an, 710061, Shaanxi, People's Republic of China.
Department of Pharmacy, The 940th Hospital of Joint Logistics Support force of PLA, Lanzhou, 730050, Gansu, People's Republic of China.
Neurochem Res. 2024 Mar;49(3):785-799. doi: 10.1007/s11064-023-04080-x. Epub 2023 Dec 16.
Abundant investigations have shown that hypobaric hypoxia (HH) causes cognitive impairment, mostly attributed to oxidative stress, inflammation, and apoptosis. HPN (4'-hydroxyl-2-subsitiuted phenylnitronyl nitroxide) is an excellent free radical scavenger with anti-inflammatory and anti-apoptotic activities. Our previous study has found that HPN exhibited neuroprotective effect on HH induced brain injury. In the present study, we examined the protective effect and potential mechanism of HPN on HH-induced cognitive impairment. Male mice were exposed to HH at 8000 m for 3 days with and without HPN treatment. Cognitive performance was assessed by the eight-arm radical maze. The histological changes were assayed by Nissle staining. The hippocampus cell apoptosis was detected by Tunnel staining. The levels of inflammatory cytokines and oxidative stress markers were detected. The expression of oxidative stress, inflammation-related and apoptosis-related proteins was determined by western blot. HPN administration significantly and mitigated HH induced histological damages and spatial memory loss with the evidence of decreased working memory error (WME), reference memory error (RME), total errors (TE) and total time (TT). In addition, HPN treatment significantly decreased the content of HO and MDA, increased the levels of SOD, CAT, GSH-Px and GSH, and inhibited the synthesis of TNF-α, IL-1β and IL-6. Moreover, HPN administration could down-regulate the expression of NF-κB, TNF-α, Bax, and cleaved caspase-3 and up-regulate the expression of Nrf2, HO-1 and Bcl-2. The number of apoptotic cells was also significantly decreased in the hippocampus of mice in the HPN group. There results indicate that HPN improve HH-induced cognitive impairment by alleviating oxidative stress damage, suppressing inflammatory response and apoptosis and may be a powerful candidate compound for alleviating memory loss induced by HH.
大量研究表明，低压低氧（HH）会导致认知障碍，主要归因于氧化应激、炎症和细胞凋亡。HPN（4'-羟基-2-取代苯基硝酮基氮氧化物）是一种具有抗炎和抗凋亡活性的优秀自由基清除剂。我们之前的研究发现，HPN 对 HH 诱导的脑损伤具有神经保护作用。在本研究中，我们研究了 HPN 对 HH 诱导的认知障碍的保护作用及其潜在机制。雄性小鼠在 8000 米高空暴露于 HH 中 3 天，并用和不用 HPN 处理。通过八臂迷津评估认知表现。通过尼氏染色检测组织学变化。通过隧穿染色检测海马细胞凋亡。检测炎症细胞因子和氧化应激标志物的水平。通过 Western blot 测定氧化应激、炎症相关和细胞凋亡相关蛋白的表达。HPN 给药显著减轻 HH 诱导的组织损伤和空间记忆丧失，表现为工作记忆错误（WME）、参考记忆错误（RME）、总错误（TE）和总时间（TT）减少。此外，HPN 治疗可显著降低 HO 和 MDA 的含量，增加 SOD、CAT、GSH-Px 和 GSH 的水平，并抑制 TNF-α、IL-1β 和 IL-6 的合成。此外，HPN 给药可下调 NF-κB、TNF-α、Bax 和 cleaved caspase-3 的表达，上调 Nrf2、HO-1 和 Bcl-2 的表达。HPN 组小鼠海马中的凋亡细胞数量也显著减少。这些结果表明，HPN 通过减轻氧化应激损伤、抑制炎症反应和细胞凋亡来改善 HH 诱导的认知障碍，可能是缓解 HH 诱导的记忆丧失的有力候选化合物。
