Li Axiang, Liu Zizhen, Ali Tahir, Gao Ruyan, Luo Yanhua, Gong Qichao, Zheng Chenyou, Li Weifen, Guo Hongling, Liu Xinshe, Li Shupeng, Li Tao
College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
Institute of Forensic Injury, Institute of Forensic Bio-Evidence, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Front Mol Neurosci. 2023 Mar 15;16:1048985. doi: 10.3389/fnmol.2023.1048985. eCollection 2023.
Despite its role in inflammation and the redox system under hypoxia, the effects and molecular mechanisms of hypoxia-inducible factor (HIF) in neuroinflammation-associated depression are poorly explored. Furthermore, Prolyl hydroxylase domain-containing proteins (PHDs) regulate HIF-1; however, whether and how PHDs regulate depressive-like behaviors under Lipopolysaccharides (LPS)-induced stress conditions remain covered.
To highlight the roles and underlying mechanisms of PHDs-HIF-1 in depression, we employed behavioral, pharmacological, and biochemical analyses using the LPS-induced depression model.
Lipopolysaccharides treatment induced depressive-like behaviors, as we found, increased immobility and decreased sucrose preference in the mice. Concurrently, we examined increased cytokine levels, HIF-1 expression, mRNA levels of PHD1/PHD2, and neuroinflammation upon LPS administration, which Roxadustat reduced. Furthermore, the PI3K inhibitor wortmannin reversed Roxadustat-induced changes. Additionally, Roxadustat treatment attenuated LPS-induced synaptic impairment and improved spine numbers, ameliorated by wortmannin.
Lipopolysaccharides-dysregulates HIF-PHDs signaling may contribute to neuroinflammation-coincides depression PI3K signaling.
尽管缺氧诱导因子（HIF）在缺氧条件下的炎症和氧化还原系统中发挥作用，但其在神经炎症相关性抑郁中的作用及分子机制仍未得到充分研究。此外，含脯氨酰羟化酶结构域蛋白（PHDs）调节HIF-1；然而，在脂多糖（LPS）诱导的应激条件下，PHDs是否以及如何调节抑郁样行为仍不清楚。
为了突出PHDs-HIF-1在抑郁症中的作用及潜在机制，我们使用LPS诱导的抑郁症模型进行了行为学、药理学和生化分析。
正如我们所发现的，脂多糖处理诱导了小鼠的抑郁样行为，表现为不动时间增加和蔗糖偏好降低。同时，我们检测到LPS给药后细胞因子水平升高、HIF-1表达增加、PHD1/PHD2的mRNA水平升高以及神经炎症，而罗沙司他可降低这些指标。此外，PI3K抑制剂渥曼青霉素可逆转罗沙司他诱导的变化。另外，罗沙司他治疗减轻了LPS诱导的突触损伤并改善了棘突数量，渥曼青霉素可改善这一情况。
脂多糖失调的HIF-PHDs信号可能导致神经炎症并发抑郁症的PI3K信号通路异常。
