Regulatory Role of NF-κB on HDAC2 and Tau Hyperphosphorylation in Diabetic Encephalopathy and the Therapeutic Potential of Luteolin

Diabetic encephalopathy (DE) is a severe complication of the central nervous system associated with diabetes. In this study, we investigated the regulatory role of mammalian target of rapamycin (mTOR) on nuclear factor κB (NF-κB) in mice with DE, and the neuroprotective effect and therapeutic mechanisms of luteolin, a natural flavonoid compound with anti-inflammatory, antioxidant, and neuroprotective properties. The results indicated that treatment with luteolin improved the degree of cognitive impairment in mice with DE. It also decreased the levels of phosphorylated mTOR, phosphorylated NF-κB, and histone deacetylase 2 (HDAC2) and increased the expression of brain-derived neurotrophic factor and synaptic-related proteins. Furthermore, protein-protein interaction and the Gene Ontology analysis revealed that luteolin was involved in the regulatory network of HDAC2 expression through the mTOR/NF-κB signaling cascade. Our bioinformatics and molecular docking results indicated that luteolin may also directly target HDAC2, as an HDAC2 inhibitor, to alleviate DE, complementing mTOR/NF-κB signaling inhibition. Analysis of luteolin’s target proteins and their interactions suggest an effect on HDAC2 and cognition. In conclusion, HDAC2 and tau hyperphosphorylation are regulated by the mTOR/NF-κB signaling cascade in DE, and luteolin is found to reverse these effects, demonstrating its protective role in DE.

• Luteolin’s neuroprotective effect on diabetic encephalopathy (DE) targets mTOR/NF-κB signaling.

• Decreases in phosphorylated mTOR, phosphorylated NF-κB, and HDAC2, and increases in brain-derived neurotrophic factor and synaptic proteins were demonstrated.

• Luteolin’s potential direct targeting to HDAC2 is highlighted, providing a new approach for DE treatment.