Huang Xin-Le, Hu Yu, Jiang Wu, Jiang Jia-Mei, Zou Wei, Zhang Ping, Tang Xiao-Qing
The Second Affiliated Hospital, Department of Neurology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, PR China.
The First Affiliated Hospital, Institute of Neurology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, PR China; Sichuan Provincial Women's and Children's Hospital/The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, 610041, Sichuan, PR China.
Exp Neurol. 2025 Mar;385:115093. doi: 10.1016/j.expneurol.2024.115093. Epub 2024 Dec 19.
Cognitive dysfunction is the most severe non-motor symptom of Parkinson's disease (PD). Our previous study revealed that hydrogen sulfide (HS) ameliorates cognitive dysfunction in PD, but the underlying mechanisms remain unclear. Hippocampal necroptosis plays a vital role in cognitive dysfunction, while the cGAS/STING pathway triggers necroptosis. To understand the mechanism underlying the inhibitory role of HS in cognitive dysfunction of PD, we explored whether HS reduces the enhancement of necroptosis and the activation of the cGAS/STING pathway in the hippocampus of the rotenone (ROT)-induced PD rat model.
Adult Sprague-Dawley (SD) rats were pre-treated with NaHS (30 or 100 μmol/kg/d, i.p.) for 7 days and then co-treated with ROT (2 mg/kg/d, s.i.) for 35 days. The Y-maze and Morris water maze (MWM) tests were used to assess the cognitive function. Hematoxylin-eosin (H&E) staining was used to detect the hippocampal pathological morphology. Western blotting analysis was used to measure the expressions of proteins. Enzyme-linked immunosorbent assay was used to determine the levels of inflammatory factors.
NaHS (a donor of HS) mitigated cognitive dysfunction in ROT-exposed rats, according to the Y-maze and MWM tests. NaHS treatment also markedly down-regulated the expressions of necroptosis-related proteins (RIPK1, RIPK3, and MLKL) and decreased the levels of necroptosis-related inflammatory factors (IL-6 and IL-1β) in the hippocampus of ROT-exposed rats. Furthermore, NaHS treatment reduced the expressions of cGAS/STING pathway-related proteins (cGAS, STING, p-TBK1, p-IRF3, and p-P65) and decreased the contents of pro-inflammation factors (INF-β and TNF-α) in the hippocampus of ROT-exposed rats.
HS attenuates the cGAS/STING pathway-triggered necroptosis in the hippocampus, which is related to HS to attenuate cognitive dysfunction in PD.
认知功能障碍是帕金森病（PD）最严重的非运动症状。我们之前的研究表明，硫化氢（HS）可改善PD患者的认知功能障碍，但其潜在机制仍不清楚。海马坏死性凋亡在认知功能障碍中起重要作用，而cGAS/STING通路可触发坏死性凋亡。为了解HS对PD认知功能障碍抑制作用的潜在机制，我们探讨了HS是否能减轻鱼藤酮（ROT）诱导的PD大鼠模型海马中坏死性凋亡的增强及cGAS/STING通路的激活。
成年Sprague-Dawley（SD）大鼠先腹腔注射硫氢化钠（NaHS，30或100 μmol/kg/d）预处理7天，然后与ROT（2 mg/kg/d，皮下注射）共同处理35天。采用Y迷宫和Morris水迷宫（MWM）试验评估认知功能。苏木精-伊红（H&E）染色检测海马病理形态。蛋白质印迹分析检测蛋白质表达。酶联免疫吸附测定法测定炎症因子水平。
根据Y迷宫和MWM试验，NaHS（HS供体）减轻了ROT暴露大鼠的认知功能障碍。NaHS处理还显著下调了ROT暴露大鼠海马中坏死性凋亡相关蛋白（RIPK1、RIPK3和MLKL）的表达，并降低了坏死性凋亡相关炎症因子（IL-6和IL-1β）的水平。此外，NaHS处理降低了ROT暴露大鼠海马中cGAS/STING通路相关蛋白（cGAS、STING、p-TBK1、p-IRF3和p-P65）的表达，并降低了促炎因子（INF-β和TNF-α）的含量。
HS减弱了海马中cGAS/STING通路触发的坏死性凋亡，这与HS减轻PD认知功能障碍有关。
