Identification of innovative therapeutic targets for the treatment of cognitive impairment in Parkinson’s disease (PD) is urgently needed. Hydrogen sulfide (H₂S) plays an important role in cognitive function. Therefore, this work is aimed at investigating whether H₂S attenuates the cognitive impairment in PD and the underlying mechanisms. In the rotenone‐ (ROT‐) established PD rat model, NaHS (a donor of H₂S) attenuated the cognitive impairment and promoted microglia polarization from M1 towards M2 in the hippocampus of PD rats. NaHS also dramatically upregulated the Warburg effect in the hippocampus of PD rats. 2‐Deoxyglucose (2‐DG, an inhibitor of the Warburg effect) abolished NaHS‐upregulated Warburg effect in the hippocampus of PD rats. Moreover, the inhibited hippocampal Warburg effect by 2‐DG abrogated H₂S‐excited the enhancement of hippocampal microglia M2 polarization and the improvement of cognitive function in ROT‐exposed rats. Our data demonstrated that H₂S inhibits the cognitive dysfunction in PD via promoting microglia M2 polarization by enhancement of hippocampal Warburg effect.

Hyperglycemia, a key characteristic and risk factor for diabetes mellitus (DM), causes neuronal senescence. Hydrogen sulfide (H₂S) is a novel neuroprotectant. The present work was to investigate the potential effect of H₂S on hyperglycemia-induced neuronal senescence and the underlying mechanisms. We found that NaHS, a donor of H₂S, inhibited high glucose (HG)-induced cellular senescence in HT22 cells (an immortalized mouse hippocampal cell line), as evidenced by a decrease in the number of senescence associated-β-galactosidase (SA-β-gal) positive cells, increase in the growth of cells, and down-regulations of senescence mark proteins, p16^INK4a and p21^CIP1. NaHS improved the autophagic flux, which is judged by a decrease in the amount of intracellular autophagosome as well as up-regulations of LC3II/I and P62 in HG-exposed HT22 cells. Furthermore, blocked autophagic flux by chloroquine (CQ) significantly abolished NaHS-exerted improvement in the autophagic flux and suppression in the cellular senescence of GH-exposed HT22 cells, which indicated that H₂S antagonizes HG-induced neuronal senescence by promoting autophagic flux. We also found that NaHS up-regulated the expression of silent mating type information regulation 2 homolog 1 (SIRT1), an important anti-aging protein, in HG-exposed HT22 cells. Furthermore, inhibition of SIRT1 by sirtinol reversed the protection of H₂S against HG-induced autophagic flux blockade and cellular senescence in HT22 cells. These data indicated that H₂S protects HT22 cells against HG-induced neuronal senescence by improving autophagic flux via up-regulation of SIRT1, suggesting H₂S as a potential treatment strategy for hyperglycemia-induced neuronal senescence and neurotoxicity.

Corticosterone (CORT) damages hippocampus neurons as well as induces neuroinflammation. Tricarboxylic acid cycle metabolite itaconate has an anti-inflammatory role. Necroptosis acts as programmed cell death triggering neuroinflammation. The deficiency of Menin, a multifunctional scaffold protein, aggravates neuroinflammation. In this study, we explored whether itaconate inhibits CORT-induced neuroinflammation and necroptosis as well as the mediatory role of Menin in this protective effect of itaconate using an exposure of CORT to HT22 hippocampal neuronal cells. The viability of HT22 cells was examined by the Cell Counting Kit 8 (CCK-8). The morphology of HT22 cells was observed by transmission electron microscope (TEM). The expressions of necroptosis-related proteins (p-RIP1/ RIP1, p-RIP3/ RIP3, and p-MLKL/ MLKL) were evaluated by Western blotting. The contents of inflammatory factors were detected by an enzyme-linked immunosorbent assay kit. Our results showed that CORT increases the contents of pro-inflammatory factors (IL-1β, TNF-α) as well as decreases the contents of anti-inflammatory factors (IL4, IL10) in HT22 cells. We also found that CORT increases the expressions of necroptosis-related proteins (p-RIP1/ RIP1, p-RIP3/ RIP3, and p-MLKL/ MLKL) and decreases the cell viability in HT22 cells, indicating that CORT induces necroptosis to HT22 cells. Itaconate improves CORT-induced neuroinflammation and necroptosis. Furthermore, itaconate upregulates the expression of Menin in CORT-exposed HT22 cells. Importantly, silencing Menin abolishes the antagonistic effect of itaconate on CORT-induced necroptosis and neuroinflammation. In brief, these results indicated that itaconate protects HT22 cells against CORT-induced neuroinflammation and necroptosis via upregulating Menin.