Punicalagin Ameliorates Diabetic Cognitive Dysfunction by Inhibiting Neuroinflammation via the <scp>CX3CL1</scp> / <scp>CX3CR1</scp> Axis

Diabetic cognitive dysfunction is a major complication of type 2 diabetes mellitus, with no effective therapy available. Punicalagin, a polyphenol compound, has demonstrated neuroprotective effects. This study aimed to explore the mechanism by which punicalagin ameliorates diabetic cognitive dysfunction, focusing on the inhibition of neuroinflammation. The type 2 diabetes mellitus model was established in vivo using a high-fat diet combined with a streptozotocin injection, and in vitro using hyperglycemic conditions. The diabetic mice received punicalagin pretreatment for 10 weeks. HT22 and BV2 cells under hyperglycemic conditions were pretreated with punicalagin for 48 h. Underlying mechanisms were investigated using the Morris water maze test, western blotting, cellular immunofluorescence and co-culture systems. Punicalagin reduced high blood glucose levels, alleviated learning and memory impairment, and attenuated neuroinflammation in diabetic mice. In addition, punicalagin promoted the expression of the CX3CL1/CX3CR1 axis and the Nrf2/HO-1 pathway. Furthermore, the inhibitory effect of punicalagin on BV2 cell-mediated neuroinflammation was attenuated after the inhibition of CX3CL1/CX3CR1 axis expression. These findings suggest that punicalagin ameliorates cognitive dysfunction and neuronal damage by attenuating neuroinflammation through activation of the CX3CL1/CX3CR1 signaling axis, offering a promising therapeutic strategy for diabetic cognitive dysfunction.