Laboratory of Regulation of Brain Neuron Functions, Pavlov Institute of Physiology RAS, Russian Academy of Sciences, Makarova emb. 6, Saint-Petersburg, Russian Federation, 199034.
Department of Biochemistry, Faculty of Biology, Saint-Petersburg State University, Universitetskaya emb. 7-9, Saint-Petersburg, Russian Federation, 199034.
Neurochem Res. 2019 Jun;44(6):1425-1436. doi: 10.1007/s11064-018-2681-x. Epub 2018 Nov 17.
Post-conditioning is exposure of an injured organism to the same harmful factors but of milder intensity which mobilizes endogenous protective mechanisms. Recently, we have developed a novel noninvasive post-conditioning (PostC) protocol involving three sequential episodes of mild hypobaric hypoxia which exerts pronounced neuroprotective action. In particular, it prevents development of pathological cascades caused by severe hypobaric hypoxia (SH) such as cellular loss, lipid peroxidation, abnormal neuroendocrine responses and behavioural deficit in experimental animals. Development of these post-hypoxic pathological effects has been associated with the delayed reduction of hypoxia-inducible factor 1 (HIF1) regulatory α-subunit levels in rat hippocampus, whereas PostC up-regulated it. The present study has been aimed at experimental examination of the hypothesis that intrinsic mechanisms underlying the neuroprotective and antioxidant effects of PostC involves HIF1-dependent stimulation of the pentose phosphate pathway (PPP). We have observed that SH leads to a decrease of glucose-6-phosphate dehydrogenase (G6PD) activity in the hippocampus and neocortex of rats as well as to a reduction in NADPH and total glutathione levels. This depletion of the antioxidant defense system together with excessive lipid peroxidation during the reoxygenation phase resulted in increased oxidative stress and massive cellular death observed after SH. In contrast, PostC led to normalization of G6PD activity, stabilization of the NADPH and total glutathione levels and thereby resulted in recovery of the cellular redox state and prevention of neuronal death. Our data suggest that stabilization of the antioxidant system via HIF1-associated PPP regulation represents an important neuroprotective mechanism enabled by PostC.
预处理是将受伤的机体暴露于相同的有害因素中，但强度较轻，从而动员内源性保护机制。最近，我们开发了一种新的非侵入性预处理（PostC）方案，涉及三个轻度低氧的连续阶段，可发挥明显的神经保护作用。特别是，它可以防止严重低氧（SH）引起的病理级联反应的发展，如细胞丢失、脂质过氧化、异常神经内分泌反应和实验动物的行为缺陷。这些低氧后病理效应的发展与大鼠海马中缺氧诱导因子 1（HIF1）调节α亚基水平的延迟降低有关，而 PostC 则上调了它。本研究旨在通过实验检验这样一种假设，即 PostC 的神经保护和抗氧化作用的内在机制涉及 HIF1 依赖性刺激戊糖磷酸途径（PPP）。我们观察到，SH 导致大鼠海马和新皮层中的葡萄糖-6-磷酸脱氢酶（G6PD）活性降低，以及 NADPH 和总谷胱甘肽水平降低。这种抗氧化防御系统的耗竭以及再氧化阶段过度的脂质过氧化导致 SH 后观察到的氧化应激增加和大量细胞死亡。相比之下，PostC 导致 G6PD 活性正常化，NADPH 和总谷胱甘肽水平稳定，从而恢复细胞氧化还原状态并防止神经元死亡。我们的数据表明，通过 HIF1 相关 PPP 调节稳定抗氧化系统代表了 PostC 启用的重要神经保护机制。
