DCI improves diabetic encephalopathy by modulating the BDNF/NF-κB/GSK-3β pathway

Diabetic encephalopathy (DE) involves cognitive dysfunction and structural brain changes due to diabetes, with a complex pathogenesis and no specific treatments available. D-chiral inositol (DCI), a bioactive molecule from dietary sources, has hypoglycemic and anti-inflammatory effects, but its role in DE and the mechanisms involved are still unclear. This study focused on male db/db mice, treated continuously with D-chiral inositol (DCI) at doses of 35 and 70 mg/kg/day for 8 weeks. Cognitive function was evaluated using the Morris water maze test, while pathological changes in the hippocampus and cortex were assessed through hematoxylin-eosin (HE) staining and Nissl staining. Protein expression related to synapses, inflammation, apoptosis, and neurofibrillary tangles, as well as mRNA levels, were analyzed using qRT-PCR, immunohistochemistry, and Western blotting to evaluate DCI's effects on DE. The results showed that DCI improved learning and memory in db/db mice, reduced nuclear pyknosis and neuronal loss, normalized PSD95 and SYN protein levels, and modulated inflammatory and apoptosis-related factors in the hippocampus and cortex. Additionally, DCI increased the expression of BDNF, IκB-α, and p-GSK-3β (Ser9), while decreasing levels of NF-κB p65, p-GSK3 (α + β) (Y216 + Y279), P-Tau (Thr231), and P-Tau (Ser396). These findings suggest that DCI may alleviate DE by modulating the BDNF/NF-κB/GSK-3β signaling pathway.