Elucidation of Neuroprotective Effect of Antidiabetic Drugs on Brain in Aβ-Induced Alzheimer’s disease Mouse Model

Abstract

Alzheimer’s disease (AD) the most common form of dementia is characterized by chronic neurodegeneration in the brain that results in a slow decline in memory and other cognitive skills accompanied with neuroinflammation. Evidences suggested that alterations in adult hippocampal neurogenesis may also contribute in cognitive deficits in AD. Recent studies have reported AD as a metabolic disease, primarily due to the aberrations in insulin. The present study elucidates the neuroprotective effect of metformin, a commonly prescribed antidiabetic in comparison to donepezil, an acetyl choline esterase inhibitor in amyloid beta (Aβ) -induced mouse model of neurodegeneration. The male Balb/c mice were divided into six groups (n=8 each group): Group 1(control), Group 2 (Aβ (1-40) -treated (1µg/µl)), Group 3 (donepezil- treated (15mg/kg)), Group 4 (metformin-treated (300mg/kg), Group 5 (Aβ (1-40) + donepezil (15mg/kg)), and Group 6 (Aβ (1µg/µl) + metformin (300mg/kg). Aβ (1µg/µl) was injected directly in hippocampus via stereotaxic surgery. After four hrs post-surgery, Metformin (300mg\kg) and Donepezil (15mg/kg) were administered consecutively for 15 days. Behavioral analysis was performed to analyze spatial memory, anxiety and depression like behavior through Morris water maze, elevated plus maze and novel object followed by histological and immunohistochemical analysis. Expression of neurogenesis (Ki67 and NeuN) and inflammatory markers (IL-6, TNF-α and GFAP) was quantified via qRT –PCR. The results demonstrated a significant cognitive decline and memory deficits in AD model. Interestingly, treatment with metformin normalized the expression levels of neurogenesis (Ki67 and NeuN) and inflammatory markers (IL-6, TNF-α and GFAP) along with improvement in the spatial memory. Moreover, metformin also increases the number of NeuN and Ki-67 cells in the hippocampus of Aβ-exposed animals. These results suggest that metformin-mediated adult hippocampal neurogenesis may have implications as a compensatory mechanism to overcome the burden of neurodegeneration. Furthermore, these significant effects of metformin on the expression of inflammatory markers make it a promising suppressor of inflammatory process in AD. These preliminary findings on the effects of metformin and donepezil provide a baseline data to strategize an alternate combination therapy to combat the deleterious effects of AD. However in depth analysis is still needed to explore the underlying mechanism of xAbstract action of metformin in mediating these important neurological processes involved in AD pathology.