Hydrogen Sulfide Protects Against Cognitive Dysfunction In Parkinson Disease Via Upregulation Of Hippocampal Warburg Effect

[Background and Objective]The progression of Parkinson's disease?PD?is accompanied by the appearance of cognitive dysfunction.At present,there is no effective drug to ameliorate the cognitive impairment in PD.Hydrogen sulfide?H2S?,as a novel recognized gasotransmitter,protects against cognitive dysfunction.Warburg effect,namely aerobic glycolysis,acts a crucial role in regulating learning and memory.Therefore,the present work was to explore whether H₂S protects against cognitive dysfunction in PD and whether its mechanism involves regulation of hippocampal Warburg effect.[Methods]1.Rats were subcutaneously injected with rotenone?ROT?to establish PD model.2.The cognitive functions of rats were evaluated by Y-maze test,novel object recognition?NOR?test,and Morris water maze?MWM?test.3.The expressions of Warburg effect-associated proteins including hexokinase II?HKII?,pyruvate kinase M2?PKM2?,lactate dehydrogenase A?LDHA?,pyruvate dehydrogenase kinase 1?PDK-1?,and pyruvate dehydrogenase?PDH?were detected by western blot.4.The level of lactate in the hippocampus was analyzed by lactate assay kit.[Results] 1.H₂S antagonizes the cognitive impairment in ROT-induced PD rats.NaHS?30,100 ?mol/kg,i.p.,4 w?markedly increased the alternation performance in Y-maze test and discrimination index in NOR test of ROT-induced PD rats,respectively.Furthermore,NaHS?30,100 ?mol/kg,i.p.,4 w?significantly shortened the latency to find the platform in the acquisition phase and increased the times of crossing the target platform as well as the time spent in the target quadrant in the probe trial in the MWM test of ROT-induced PD rats.Taken together,H₂S protects against cognitive dysfunction in ROT-induced PD rats.2.H₂S upregulates Warburg effect in the hippocampus of ROT-exerted PD rats.NaHS?30,100 ?mol/kg,i.p.,4 w?dramatically ameliorated ROT-exerted decline in the expressions of HKII,PKM2,LDHA,and PDK-1 as well as elevation in the expression of PDH.Furthermore,NaHS?30,100 ?mol/kg,i.p.,4 w?effectively increased the level of lactate in the hippocampus of ROT-exposed rats.These data implied that H₂S upregulated Warburg effect in the hippocampus of ROT-elicited PD rats.3.2-deoxyglucose?2-DG?inhibits the up-regulatory role of H₂S on Warburg effect in the hippocampus of ROT-induced PD rats.Treatment with 2-DG?3 ?g/w,i.c.v,3 w?markedly decreased the expressions of HKII,PKM2,PDK-1,and LDHA as well as increased the expression of PDH in the co-treated with ROT and NaHS rats.In addition,2-DG?3 ?g/w,i.c.v.,3 w?obviously revered the role of NaHS?100 ?mol/kg,i.p.,4 w?in enhancing lactate content in the hippocampus of ROT-induced PD rats.These results indicated that 2-DG alleviates H2S-enhanced Warburg effect in the hippocampus of ROT-induced PD rats.4.Inhibition of hippocampal Warburg effect reverses the antagonistic action of H₂S in the cognitive dysfunction of ROT-exerted PD rats2-DG?3 ?g/w,i.c.v,3 w?dramatically reversed the up-regulatory effect of NaHS?100 ?mol/kg,i.p.,4 w?on the alternative performance in Y-maze test and the recognition index in NOR test of ROT-induced PD rats.Furthermore,the data from the acquisition phase in MWM test exhibited that 2-DG significantly increased the latency to find platform in the rats cotreated with ROT and NaHS.The probe trail test in MWM test showed that 2-DG decreased the times of crossing the target platform and the time spent in the target quadrant in the rats cotreated with ROT and NaHS.Taken together,inhibiting hippocampal Warburg effect abrogated the protection of H₂S against the cognitive impairment in ROT-exerted PD rats.[Conclusion]1.H₂S inhibits the cognitive dysfunction in ROT-induced PD rats.2.Hippocampal Warburg effect mediates the inhibitory role of H₂S in the cognitive dysfunction of ROT-induced PD rats.