Punicalagin Attenuates Neuronal Apoptosis by Upregulating 5-Hydroxymethylcytosine in the Diabetic Mouse Brain

Punicalagin exerts neuroprotective activity by improving AMP-activated kinase (AMPK) and mitochondrial Krebs cycle. AMPK and Krebs cycle metabolites regulate 5-hydroxymethylcytosine (5hmC) via acting on ten-eleven translocation (TET) enzymes. Therefore, we hypothesized that punicalagin inhibits diabetes-related neuronal apoptosis by upregulating 5hmC in the diabetic mouse brain. C57BL/6J mice aged 8 weeks were randomly separated into five groups (n = 10), normal control (NC), diabetes mellitus (DM), resveratrol (RES), low-dose punicalagin (LPU), and high-dose punicalagin (HPU). Compared with other groups, the neuronal apoptosis rate was significantly higher and the 5hmC level of the cerebral cortex was significantly lower in the DM group. The levels of TET2 and P-AMPK alpha/AMPK alpha were significantly lower in the DM group than in both LPU and HPU groups. The ratio of (succinic acid + fumaric acid)/alpha-ketoglutarate was significantly higher in the DM group than in other groups. The present results suggest that punicalagin upregulates 5hmC via activating AMPK and maintaining Krebs cycle homeostasis, thus inhibiting neuronal apoptosis in the diabetic mouse brain.

Automated summary

This study found that punicalagin inhibits diabetes-related neuronal apoptosis by upregulating 5hmC levels through activating AMPK and maintaining Krebs cycle homeostasis in the diabetic mouse brain.