Comparative Study of Effects of Metformin and Donepezil in AlCl3 Induced Oxidative Stress in the Brain of AD Mouse Models

Abstract

Alzheimer’s Disease (AD) is a polygenic progressive neurological disorder which effect about 45 million people worldwide. It is characterized by the deposition of amyloid beta (A) plaques and neurofibrillary tangles (NFTs) in the brain. The FDA approved drugs for AD temporarily slower the progression of the disease however there are no therapeutic drugs that permanently inhibit progression or reverse the neural degradation in AD. Emerging evidence indicated molecular association between diabetes mellitus type 2 (T2DM) and AD that led to examine the effects of several anti diabetic medications against AD. In this study, we performed a comparative assessment of therapeutic effects of Metformin, a widely prescribed anti diabetic drug and Donepezil, a classical drug for AD that inhibit cholinesterase and in turn up-regulate acetylcholine thus enhancing cholinergic transmission. The aluminium chloride (AlCl3)-induced neurotoxicity mouse models were used to study AD associated aberrations and were placed into two groups treated with Donepezil and Metformin (n=8, each group), while the control group was administered distilled water only. A 2- Dimensional Gel electrophoresis and SDS-PAGE analysis was performed to evaluate the differentially expressed proteins in the treated groups. AlCl3 induced the formation of A plaques in hippocampus, whereas significant differences were observed in Donepezil and Metformin-treated groups evident through histological assessment of the treated tissue sections. Interestingly, Metformin-treatment reduced the A plaques formation and normalized the protein expression pattern. Moreover, molecular docking analysis was also performed to compare the binding potential of Donepezil and Metformin with pathologically significant proteins involved in AD associated molecular dysregulation. Interestingly, Metformin showed strong binding affinity with xii the target proteins. Doublecortin (DCX), Presinilin (PSEN1), and Ki-67 showed the most stable conformations in comparison to Donepezil. In conclusion, these findings reemphasize proteomic alterations in AD and suggested a potential effect of antidiabetic drug on aberrant protein expression which provides basis for future drug repurposing for better therapeutic interventions for AD