{"title":"Suppression of cGAS/STING pathway-triggered necroptosis in the hippocampus relates H<sub>2</sub>S to attenuate cognitive dysfunction of Parkinson's disease.","authors":"Xin-Le Huang, Yu Hu, Wu Jiang, Jia-Mei Jiang, Wei Zou, Ping Zhang, Xiao-Qing Tang","doi":"10.1016/j.expneurol.2024.115093","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Cognitive dysfunction is the most severe non-motor symptom of Parkinson's disease (PD). Our previous study revealed that hydrogen sulfide (H<sub>2</sub>S) 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 H<sub>2</sub>S in cognitive dysfunction of PD, we explored whether H<sub>2</sub>S reduces the enhancement of necroptosis and the activation of the cGAS/STING pathway in the hippocampus of the rotenone (ROT)-induced PD rat model.</p><p><strong>Method: </strong>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.</p><p><strong>Result: </strong>NaHS (a donor of H<sub>2</sub>S) 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<sup>Ser172</sup>, p-IRF3<sup>Ser396</sup>, and p-P65<sup>Ser536</sup>) and decreased the contents of pro-inflammation factors (INF-β and TNF-α) in the hippocampus of ROT-exposed rats.</p><p><strong>Conclusion: </strong>H<sub>2</sub>S attenuates the cGAS/STING pathway-triggered necroptosis in the hippocampus, which is related to H<sub>2</sub>S to attenuate cognitive dysfunction in PD.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115093"},"PeriodicalIF":4.6000,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.expneurol.2024.115093","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
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-TBK1Ser172, p-IRF3Ser396, and p-P65Ser536) 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.
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.
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