Hydrogen Sulfide Ameliorates Cognitive Dysfunction In Parkinson’s Disease Rats:Involving Inhibition Of Hippocampal Necroptosis And CGAS-STING Pathway

[Background and Objective]Parkinson’s disease（PD）is the second most common neurodegenerative disease,of which cognitive impairment is the most severe non-motor symptom.It has been confirmed that hydrogen sulfide（H₂S）,an important neuromodulatory molecule,has the function to alleviate the cognitive impairment in PD rats,but the mechanism of this protective effect has not been elucidated.It has been reported that necroptosis in hippocampus is responsible for cognitive dysfunction and that cGAS-STING pathway triggeres necroptosis.In order to clarify the mechanisms underlying the protection of H₂S against the cognitive impairment in PD,we explore the effects of H₂S on necroptosis and cGAS-STING pathway in the hippocampus of PD rats established by rotenone（ROT）.[Methods]1.Male Sprague-Dawley（SD）rats were injected with ROT in the neck to construct the PD rat model.2.Y-maze and Morris water maze（MWM）tests were used to detect the cognitive function of rats.3.Hematoxylin-eosin staining was used to detect the histopathological morphology of hippocampus.4.Western blot was used to detect the expressions of necroptosis related proteins（p-RIP1,p-RIP3,and p-MLKL）and cGAS-STING pathway related proteins（cGAS,STING,p-TBK1,p-IRF3,and p-P65）in the hippocampus.5.Enzyme-linked immuno sorbent assay was used to measure the contents of interleukin-6（IL-6）,interleukin-1β（IL-1β）,interferon beta（IFN-β）,and tumor necrosis factor-alpha（TNF-α）in the hippocampus.[Results]1.H₂S alleviates the cognitive impairment in ROT-induced PD ratsROT（2 mg/kg）treatment reduced the spontaneous alternation rate of SD rats in the Y-maze test,and the number of platform crossings as well as the time staying at target quadrant in the WMW test,indicating that the PD-related cognitive impairment rat model was successfully established.Na HS（30 or 100μmol/kg,i.p.）reversed the reduction of spontaneous alternation rate in the Y-maze test,and the decreases in the number of platform crossings as well as the time staying at the target quadrant in the WMW test,indicating the antagonism of H₂S on the cognitive impairment in PD.2.H₂S suppresses the necroptosis in the hippocampus of PD rats with cognitive impairmentIn the hippocampus of PD rats with cognitive impairment induced by ROT,the pathological injury,the expressions of necroptosis related proteins（p-RIP1,p-RIP3,and p-MLKL）,and the contents of necroptosis related inflammatory factors（IL-6 and IL-1β）were increased.However,Na HS（30 or 100μmol/kg,i.p.）treatment decreased the pathological injury,the expressions of necroptosis related proteins（p-RIP1,p-RIP3,and p-MLKL）,and the contents of necroptosis related inflammatory factors（IL-6 and IL-1β）in the hippocampus of PD rats with cognitive impairment induced by ROT,which indicated that H₂S suppresses the hippocampal necroptosis in the PD rats with cognitive impairment.3.H₂S inhibits the cGAS-STING pathway in the hippocampus of PD rats with cognitive impairmentIn the hippocampus of PD rats with cognitive impairment induced by ROT,the expressions of cGAS-STING pathway key proteins（cGAS and STING）,the expressions of cGAS-STING pathway related proteins（p-TBK1,p-IRF3,and p-P65）,and the contents of cGAS-STING pathway products（IFN-βand TNF-α）were increased.However,Na HS（30 or 100μmol/kg,i.p.）treatment decreased the expressions of cGAS,STING,p-TBK1,p-IRF3,and p-P65,and the contents of IFN-βas well as TNF-α.Taking together,H₂S inhibits hippocampal cGAS-STING pathway in the PD rats with cognitive impairment.[Conclusion]The inhibitory effect of H₂S on cognitive impairment in PD rats is associated with the inhibition of necroptosis and cGAS-STING pathway in the hippocampus.