Neuroprotective effects of lithium and caffeic acid co-loaded liposomes in diabetes-induced Alzheimer's disease: association with GSK-3β and β-catenin

AIM: To investigate the therapeutic effects of co-loaded lithium (Li) and caffeic acid (CA) liposomes in diabetes-induced Alzheimer's disease rats by improving cognitive dysfunction and attenuating neurodegeneration through the modulation of β-catenin/GSK-3β signaling. METHODS: Li- and CA-co-loaded liposomes were prepared by the ethanol injection method and characterized. A diabetes-induced Alzheimer's disease model was established in male Wistar rats using a high-fat diet followed by low-dose streptozotocin (35 mg/kg) administered intraperitoneally. Li- and CA-co-loaded liposomes were given via the same route every day for 4 weeks. At the end of the experiment, the animals were sacrificed, and various biochemical and oxidative stress parameters, histopathological assessments, and ELISA analyses were performed. RESULTS: Dual-drug-loaded Li and CA liposomal treatment significantly improved cognitive function, ameliorated metabolic dysfunction, and reduced oxidative stress by restoring antioxidant enzyme levels. Additionally, liposomes attenuated nitrite, acetylcholinesterase, and amyloid-β levels in diabetes-induced Alzheimer's rats. Histopathological assessment confirmed marked neuroprotective and pancreatic protective effects. Further, at a molecular level, Li and CA liposomal treatment reduced the expression of GSK-3β and increased the expression of β-catenin levels in rats. CONCLUSION: This study provides the first evidence demonstrating the therapeutic potential of Li- and CA-co-loaded liposomes in attenuating diabetes‑associated cognitive dysfunction.