Neuroprotective potential of Prunetin in streptozotocin-induced cognitive dysfunction: insights from computational and experimental studies.

BACKGROUND: Type 2 diabetes mellitus (T2DM) accounts for over 85% of global diabetes cases and is strongly associated with cognitive decline resulting from chronic hyperglycemia-induced neuronal and oxidative damage. Prunetin, a natural isoflavone known for potent antioxidant and antidiabetic activity, was investigated for its potential to attenuate diabetes-associated cognitive deficits. METHODS: In silico analysis included molecular docking, MM-GBSA binding free energy, and molecular dynamics simulations (100 ns) to explore interactions between Prunetin and human acetylcholinesterase (AChE; PDB ID: 7D9O). In vivo studies were conducted in streptozotocin (STZ)-induced diabetic rats, with cognition assessed using the Morris water maze. Brain tissues were examined for Aβ(1-42), lipid peroxidation, reduced glutathione (GSH), and AChE activity to determine oxidative status and cholinergic function. RESULTS: Prunetin (0.5 mg/kg/day) administered for 14 (acute) or 28 days (chronic) reduced blood glucose levels, Aβ(1-42) accumulation, and lipid peroxidation while increasing GSH levels and inhibiting AChE activity in a duration-dependent manner. These effects corresponded with significant improvements in Morris water maze performance, with 28-day treatment demonstrating greater efficacy than the 14-day regimen for most parameters. Computational modeling confirmed stable Prunetin-AChE complex formation mediated by hydrogen bonding, hydrophobic interactions, and π-π stacking interactions. CONCLUSION: Prunetin demonstrates notable antioxidant and AChE-inhibitory properties, attenuating STZ-induced cognitive dysfunction in an experimental rat model. These findings collectively support Prunetin as a promising multitarget candidate warranting further investigation for diabetes-associated neurodegeneration.