The pentose phosphate pathway (PPP) of glucose metabolism in the brain serves as a primary source of NADPH which in turn plays a crucial role in multiple cellular processes, including maintenance of redox homeostasis and antioxidant defense. In our model of protective mild hypobaric hypoxia in rats (3MHH), an inverse correlation between hypoxia-inducible factor-1 (HIF1) activity and mRNA levels of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of PPP, was observed. In the present study, it was demonstrated that severe hypobaric hypoxia (SH) induced short-term upregulation of HIF1 alpha-subunit (HIF1α) in the hippocampal CA1 subfield and decreased the activity of G6PD. The levels of NADPH were also reduced, promoting oxidative stress, triggering apoptosis, and neuronal loss. Injection of a HIF1 inhibitor (HIF1i), topotecan hydrochloride (5 mg/kg, i.p.), before SH prevented the upregulation of HIF1α and normalized G6PD activity. In addition, HIF1i injection caused an increase in NADPH levels, normalization of total glutathione levels and of the cellular redox status as well as suppression of free-radical and apoptotic processes. These results demonstrate a new molecular mechanism of post-hypoxic cerebral pathology development which involves HIF1-dependent PPP depletion and support a recently suggested injurious role of HIF1 activation in the acute phase of cerebral hypoxia/ischemia. Application of PPP stimulators in early post-hypoxic/ischemic period might represent a promising neuroprotective strategy.

HIF1-dependent down-regulation of the pentose phosphate pathway contributes to the hypoxia-induced oxidative stress and neuronal apoptosis in the rat hippocampus

中文翻译：

---

药理学HIF1抑制作用消除了戊糖磷酸途径的下调并防止了严重缺氧引起的大鼠海马神经元凋亡。

脑中葡萄糖代谢的磷酸戊糖途径（PPP）是NADPH的主要来源，而NADPH则在多种细胞过程中起着至关重要的作用，包括维持氧化还原稳态和抗氧化防御。在我们的大鼠保护性轻度低压缺氧模型（3MHH）中，观察到缺氧诱导因子1（HIF1）活性与PPP关键酶葡萄糖6磷酸脱氢酶（G6PD）的mRNA水平成反比。 。在本研究中，已证明严重的低压缺氧（SH）会在海马CA1子域中引起HIF1α亚基（HIF1α）的短期上调并降低G6PD的活性。NADPH的水平也降低了，从而促进了氧化应激，触发了细胞凋亡和神经元丢失。注射HIF1抑制剂（HIF1i），盐酸托泊替康（5 mg / kg，腹腔注射）之前，SH阻止了HIF1α的上调和G6PD活性的正常化。此外，HIF1i注射引起NADPH水平升高，总谷胱甘肽水平和细胞氧化还原状态正常化以及自由基和凋亡过程的抑制。这些结果证明了缺氧后脑病理学发展的一种新的分子机制，涉及HIF1依赖性PPP耗竭，并支持了HIF1激活在脑缺氧/缺血急性期的最新作用。在缺氧/缺血后早期应用PPP刺激物可能代表了一种有前途的神经保护策略。总谷胱甘肽水平和细胞氧化还原状态的正常化以及自由基和凋亡过程的抑制。这些结果证明了缺氧后脑病理学发展的一种新的分子机制，涉及HIF1依赖性PPP耗竭，并支持了HIF1激活在脑缺氧/缺血急性期中的最新作用。在缺氧/缺血后早期应用PPP刺激物可能代表了一种有前途的神经保护策略。总谷胱甘肽水平和细胞氧化还原状态的正常化以及自由基和凋亡过程的抑制。这些结果证明了缺氧后脑病理学发展的一种新的分子机制，涉及HIF1依赖性PPP耗竭，并支持了HIF1激活在脑缺氧/缺血急性期的一种新的有害作用。在缺氧/缺血后早期应用PPP刺激物可能代表了一种有前途的神经保护策略。这些结果证明了缺氧后脑病理学发展的一种新的分子机制，涉及HIF1依赖性PPP耗竭，并支持了HIF1激活在脑缺氧/缺血急性期的一种新的有害作用。在缺氧/缺血后早期应用PPP刺激物可能代表了一种有前途的神经保护策略。这些结果证明了缺氧后脑病理学发展的一种新的分子机制，涉及HIF1依赖性PPP耗竭，并支持了HIF1激活在脑缺氧/缺血急性期的一种新的有害作用。在缺氧/缺血后早期应用PPP刺激物可能代表了一种有前途的神经保护策略。

HIF1依赖的戊糖磷酸途径的下调有助于低氧诱导的大鼠海马中的氧化应激和神经元凋亡