Title: P1‐223: Vildagliptin: A dipeptidyl peptidase‐IV inhibitor ameliorates Alzheimer's disease
Abstract: Diabetes is a risk factor for Alzheimer's disease (AD), and also shares some common features such as Aß aggregation, over activity of glycogen synthase kinase-3, increased oxidative stress, increased inflammation response and correlation with apolipoprotein E E4 allele. Thus some drugs acting in diabetes also promise to be useful in the prevention/reduction of AD. This is the case with glucagon-like peptide-1 (GLP-1). In diabetes, GLP-1 increases insulin secretion and β-cell proliferation, and decreases β-cell apoptosis. GLP-1 also acts on GLP-1 receptors present in different regions of brain and decreases Aß peptide and amyloid precursor protein in AD. Unfortunately GLP-1 is metabolised by the enzyme called dipeptidyl peptidase-IV (DPP-IV), which rapidly transforms GLP-1 into inactive metabolite resulting in very short half-life of intact hormone. In the present study, vildagliptin a DPP-IV inhibitor originally developed for the treatment of diabetes was evaluated against streptozotocin induced AD of murine model. AD is induced by intracerebroventricular injection of streptozotocin, administered twice with an interval of 48h. After 21 days of induction, memory was assessed by Morris water maze and radial arm maze. Vildagliptin was administered for 12 weeks from 21st day after confirming streptozotocin induced dementia. Biochemical parameters including oxidative stress, amyloid burden, GLP-1 levels, inflammatory hallmarks and apoptotic markers within the brain were evaluated. Histology of hippocampus was taken at the end of the study to determine the treatment related effects. Treatment with vildagliptin for 12 weeks significantly reduced oxidative stress, inflammation, apoptosis, and significantly increased the levels of GLP-1 in the brain. Animals treated with vildagliptin improved the memory function in maze tests. Histopathology of the hippocampus reveals the effect which supports the data favouring in the treatment of AD with vildagliptin Our results show that vildagliptin prevents key neurodegenerative developments found in AD, suggesting that DPP-IV inhibitors represent a novel treatment strategy for AD.