Hydrogen sulfide protects against hippocampal neuronal apoptosis in aged rats with postoperative cognitive dysfunction by promoting m6A methylation.

PURPOSE: To explore the potential involvement of m6A methylation in the neuroprotective mechanism of H2S against hippocampus neuronal apoptosis in aged rats with POCD.

METHODS

Sprague-Dawley rats (18-20 months) were subjected to anesthesia and laparotomy surgery to establish an animal model of POCD. The Open Field, Y-maze, and Novel Object Recognition tests assessed behavioral performance. Protein expression levels were analyzed using Western blot analysis, and neuronal apoptosis was analyzed using TUNEL staining.

RESULTS

NaHS (100 μmol/kg) significantly increased the alternation ratio of the Y-maze test and the discrimination index of the NOR test, reduced hippocampal neuronal apoptosis, indicated by decreased TUNEL-positive neurons and modulated the expression of apoptosis-related protein markers (Bcl-2 was upregulated and Bax/Cleaved caspase-3 were downregulated). Furthermore, NaHS restored reduced m6A RNA methylation levels and corrected the disturbed expression of m6A-related enzymes (METTL3, METTL14, YTHDF1, YTHDF3, FTO, ALKBH5) in the hippocampus of aged rats with POCD.

CONCLUSION

H2S shows neuroprotective effects by mitigating hippocampal neuronal apoptosis and restoring m6A RNA methylation in the hippocampus of aged rats with POCD. These findings provide preclinical evidence that H2S may serve as a potential therapeutic agent for the prevention of POCD.