title: Saxagliptin: a dipeptidyl peptidase-4 inhibitor ameliorates streptozotocin induced Alzheimer's disease.
abstract: Type 2 diabetes (T2D) is one of the major risk factors associated with Alzheimer's disease (AD). Recent studies have found similarities in molecular mechanisms that underlie the respective degenerative developments in the two diseases. Pharmacological agents, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, which increase the level of glucagon-like peptide-1 (GLP-1) and ameliorate T2D, have become valuable candidates as disease modifying agents in the treatment of AD. In addition, endogenous GLP-1 levels decrease amyloid beta (Aβ) peptide and tau phosphorylation in AD. The present study examines the efficacy of Saxagliptin, a DPP-4 inhibitor in a streptozotocin (STZ) induced rat model of AD. Three months following induction of AD by intracerebral administration of streptozotocin, animals were orally administered Saxagliptin (0.25, 0.5 and 1 mg/kg) for 60 days. The effect of the DPP-4 inhibitor on hippocampal GLP-1 levels, Aβ burden, tau phosphorylation, inflammatory markers and memory retention were evaluated. The results reveal an attenuation of Aβ, tau phosphorylation and inflammatory markers and an improvement in hippocampal GLP-1 and memory retention following treatment. This remarkable therapeutic effect of Saxagliptin mediated through DPP-4 inhibition demonstrates a unique mechanism for Aβ and tau clearance by increasing GLP-1 levels and reverses the behavioural deficits and pathology observed in AD.
authors.affiliation: Department of Pharmacognosy, JSS College of Pharmacy, Udhagamandalam, Tamilnadu 643001, India. jayasankar87@hotmail.com
authors.forename: Jayasankar
authors.initials: J
authors.lastname: Kosaraju
authors.forename: Chaitanya Chakravarthi
authors.initials: CC
authors.lastname: Gali
authors.forename: Rizwan Basha
authors.initials: RB
authors.lastname: Khatwal
authors.forename: Anil
authors.initials: A
authors.lastname: Dubala
authors.forename: Santhivardhan
authors.initials: S
authors.lastname: Chinni
authors.forename: R M Damian
authors.initials: RM
authors.lastname: Holsinger
authors.forename: V Subba Rao
authors.initials: VS
authors.lastname: Madhunapantula
authors.forename: Satish Kumar
authors.initials: SK
authors.lastname: Muthureddy Nataraj
authors.forename: Duraiswamy
authors.initials: D
authors.lastname: Basavan
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D004151:Dipeptides / Q000627:therapeutic use*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000903:Antibiotics, Antineoplastic; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D016875:tau Proteins; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1; C502994:saxagliptin; D000218:Adamantane