Lenalidomide ameliorates cognitive impairment via putative AChE inhibition: an in silico and in vivo study in a scopolamine-induced cognitive impairment model

Alzheimer's disease (AD) causes progressive cognitive decline, and current therapies provide limited benefit. This study evaluated the neuroprotective effects of lenalidomide (LLM), a thalidomide derivative, in a scopolamine-induced mouse model of cognitive impairment, with emphasis on its acetylcholinesterase (AChE) inhibitory potential. Mice received LLM (5, 10, and 20 mg/kg), donepezil (DNP) (3 mg/kg), or a combination and were assessed using Y-maze, passive avoidance, novel object recognition, and Morris water maze tests. In silico analysis, including molecular docking, 100 ns molecular dynamics simulation and ADMET profiling were performed to investigate the interaction of LLM with AChE. Memory performance showed a significant and dose-dependent improvement after the treatment of LLM. The 20 mg/kg dose exhibited effects comparable to DNP. LLM and DNP work together to increase effectiveness. Docking and simulation analyses revealed strong, stable binding to AChE while ADMET values indicated good drug-likeness. LLM exhibits neuroprotective and cognition enhancing effects in the scopolamine-induced model. In silico study also shows its potential as an AChE inhibitor. The study's anti-inflammatory mechanisms might also be helpful but need more exploration.