A Study to Investigate the Potential Role of Anti Diabetic versus Classical Acetylcholinesterase Inhibitor in Neurogenesis

Abstract

Alzheimer's disease (AD), the most common cause of dementia, is associated with neurodegeneration that is characterized initially by synaptic injury followed by neuronal loss. More recent studies have uncovered evidence, suggesting that another component to the neurodegenerative process in AD might include the possibility of interference with the process of adult neurogenesis in the hippocampus. Since growing evidence supports the notion that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin stimulation, it can be inferred that antidiabetics may serve as an alternative therapeutic strategy for AD. The present study has investigated the pro neurogenic effects of metformin (300mg/kg) in an in house generated AlCl3 induced mouse model of neurodegeneration (600mg/kg) and drawn a comparison with neurogenic potential of donepezil (15mg/kg). A morris water maze task was performed to test spatial learning, and a subsequent histopathological and immunohistochemical evaluation was conducted. Expression of neurogenesis markers (Ki67, DCX and NeuN) along with insulin expression and differential proteome analysis of hippocampus was evaluated by qRT-PCR and SDS-PAGE respectively. The aberrantly expressed proteins were subsequently identified by ESI-QTOF MS/MS and functionally associated using STRING 8.3. The results demonstrated impaired spatial memory in AlCl3 group as reflected by deviant learning curves, escape latency, and impaired probe trial performance. Histopathological assessment showed that AlCl3 exposure led to substantial decrease in the density of Nissl substances (indication of neurodegeneration) and classical appearance of shrunk neurons and vacuolation suggesting concurrent degeneration of neurons in hippocampus. Proteome profiling showed that a total of eight proteins, involved in several biologically important pathways, were differentially expressed in hippocampus. Interestingly, treatment with metformin normalized the structural changes, changes in protein expression pattern as well as the alterations in the expression levels of insulin, Ki67, DCX and NeuN. Metformin improved memory impairment and increased the number of post mitotic NeuN-positive neurons in the hippocampus of AlCl3 exposed animals. Moreover, metformin demonstrated profound effects on hippocampal neurogenesis as compared to donepezil. The results indicate that xiAbstract metformin improves cognitive function and enhances the survival of newborn neurons in the hippocampus in animal model of neurodegeneration. Furthermore, metformin associated profound pro neurogenic effects observed in this study favor metformin over donepezil with regard to neuro regenerative potential. Further elucidation of underlying molecular mechanisms of metformin mediated adult hippocampal neurogenesis is