Suppression of cGAS/STING pathway-triggered necroptosis in the hippocampus relates H2S to attenuate cognitive dysfunction of Parkinson's disease

IF 4.6 2区医学 Q1 NEUROSCIENCES Experimental Neurology Pub Date : 2024-12-19 DOI:10.1016/j.expneurol.2024.115093

Xin-Le Huang , Yu Hu , Wu Jiang , Jia-Mei Jiang , Wei Zou , Ping Zhang , Xiao-Qing Tang

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Abstract

Background

Cognitive dysfunction is the most severe non-motor symptom of Parkinson's disease (PD). Our previous study revealed that hydrogen sulfide (H₂S) 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 H₂S in cognitive dysfunction of PD, we explored whether H₂S reduces the enhancement of necroptosis and the activation of the cGAS/STING pathway in the hippocampus of the rotenone (ROT)-induced PD rat model.

Method

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.

Result

NaHS (a donor of H₂S) 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^Ser172, p-IRF3^Ser396, and p-P65^Ser536) and decreased the contents of pro-inflammation factors (INF-β and TNF-α) in the hippocampus of ROT-exposed rats.

Conclusion

H₂S attenuates the cGAS/STING pathway-triggered necroptosis in the hippocampus, which is related to H₂S to attenuate cognitive dysfunction in PD.

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抑制cGAS/STING通路引发的海马坏死性下垂与H2S减轻帕金森病认知功能障碍相关

背景：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（H2S）可以改善PD患者的认知功能障碍，但其潜在机制尚不清楚。海马坏死性上睑下垂在认知功能障碍中起着至关重要的作用，而cGAS/STING通路触发坏死性上睑下垂。为了了解H2S在PD认知功能障碍中的抑制作用机制，我们探讨了H2S是否会降低鱼藤酮（ROT）诱导的PD大鼠模型中坏死性坏死的增强和海马cGAS/STING通路的激活。方法：用NaHS（30或100 μmol/kg/d， i.p.）预处理成年SD大鼠7 d，再用ROT（2 mg/kg/d, s.i.i）共处理35 d。采用y形迷宫和Morris水迷宫（MWM）测试评估认知功能。采用苏木精-伊红（H&E）染色检测海马病理形态。Western blotting法检测蛋白表达。采用酶联免疫吸附法测定炎症因子水平。结果：根据y迷宫和MWM测试，NaHS （H2S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rot暴露大鼠海马中坏死相关蛋白（RIPK1、RIPK3和MLKL）的表达，降低坏死相关炎症因子（IL-6和IL-1β）的水平。此外，NaHS处理降低了cGAS/STING通路相关蛋白（cGAS、STING、p-TBK1Ser172、p-IRF3Ser396和p-P65Ser536）的表达，降低了rot暴露大鼠海马中促炎症因子（INF-β和TNF-α）的含量。结论：H2S可减轻cGAS/STING通路引发的海马坏死性下垂，这与H2S减轻PD认知功能障碍有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Experimental Neurology 医学-神经科学

CiteScore

10.10

自引率

3.80%

发文量

258

审稿时长

42 days

期刊介绍： Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.