<br>HDAC 抑制通过 PI3K/GSK3β/CREB 通路预防低压缺氧引起的空间记忆障碍,Journal of Cellular Physiology

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HDAC 抑制通过 PI3K/GSK3β/CREB 通路预防低压缺氧引起的空间记忆障碍
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2021-03-31 , DOI: 10.1002/jcp.30337
Rahul Kumar ₁ , Vishal Jain ₂ , Neetu Kushwah ₁ , Aastha Dheer ₁ , Kamla Prasad Mishra ₃ , Dipti Prasad ₁ , Shashi Bala Singh ₄

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高海拔地区的低压缺氧通常会损害认知功能。先前的研究表明表观遗传修饰是造成这种情况的罪魁祸首。在这里，我们着手确定低压缺氧如何介导表观遗传修饰，以及这种情况如何恶化大鼠的神经变性和记忆丧失。在当前的研究中，与对照大鼠大脑相比，不同持续时间的低压缺氧显示海马中组蛋白乙酰转移酶和组蛋白脱乙酰酶（HDAC）基因表达的离散模式。与对照大鼠海马相比，低压缺氧暴露下组蛋白 H2A、H3 和 H4 的乙酰化位点水平显着降低。此外，用丁酸钠（1.2 g/kg 体重）抑制 HDAC 家族可减轻低压缺氧大鼠的神经变性和记忆丧失。此外，脑源性神经营养因子（BDNF）启动子区域的组蛋白乙酰化增加；因此，与缺氧大鼠相比，用HDAC抑制剂治疗的低压缺氧暴露大鼠中其蛋白表达显着增强。因此，BDNF 表达通过刺激 PI3K/GSK3β/CREB 轴上调 cAMP 反应元件结合蛋白 (CREB) 磷酸化，从而抵消低压缺氧引起的空间记忆障碍。总之，这些结果表明丁酸钠是治疗与低压缺氧相关的空间记忆丧失的新型治疗剂，并且还需要进一步的研究来探索这种情况下的特异性 HDAC 抑制剂。

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HDAC inhibition prevents hypobaric hypoxia-induced spatial memory impairment through PΙ3K/GSK3β/CREB pathway

Hypobaric hypoxia at higher altitudes usually impairs cognitive function. Previous studies suggested that epigenetic modifications are the culprits for this condition. Here, we set out to determine how hypobaric hypoxia mediates epigenetic modifications and how this condition worsens neurodegeneration and memory loss in rats. In the current study, different duration of hypobaric hypoxia exposure showed a discrete pattern of histone acetyltransferases and histone deacetylases (HDACs) gene expression in the hippocampus when compared with control rat brains. The level of acetylation sites in histone H2A, H3 and H4 was significantly decreased under hypobaric hypoxia exposure compared to the control rat's hippocampus. Additionally, inhibiting the HDAC family with sodium butyrate administration (1.2 g/kg body weight) attenuated neurodegeneration and memory loss in hypobaric hypoxia-exposed rats. Moreover, histone acetylation increased at the promoter regions of brain-derived neurotrophic factor (BDNF); thereby its protein expression was enhanced significantly in hypobaric hypoxia exposed rats treated with HDAC inhibitor compared with hypoxic rats. Thus, BDNF expression upregulated cAMP-response element binding protein (CREB) phosphorylation by stimulation of PI3K/GSK3β/CREB axis, which counteracts hypobaric hypoxia-induced spatial memory impairment. In conclusion, these results suggested that sodium butyrate is a novel therapeutic agent for the treatment of spatial memory loss associated with hypobaric hypoxia, and also further studies are warranted to explore specific HDAC inhibitors in this condition.

更新日期：2021-03-31

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