Suppression of cGAS/STING pathway-triggered necroptosis in the hippocampus relates H 2 S to attenuate cognitive dysfunction of Parkinson's disease.

Background: Cognitive dysfunction is the most severe non-motor symptom of Parkinson's disease (PD). Our previous study revealed that hydrogen sulfide (H ₂ 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 ₂ S in cognitive dysfunction of PD, we explored whether H ₂ 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.
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 H ₂ 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 ^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: H ₂ S attenuates the cGAS/STING pathway-triggered necroptosis in the hippocampus, which is related to H ₂ S to attenuate cognitive dysfunction in PD.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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