title: DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats.
abstract: Recent evidence has demonstrated that insulin resistance is related to the development of type 2 diabetes mellitus. Our previous study found that high-fat diet (HFD) consumption caused not only peripheral and brain insulin resistance but also brain mitochondrial dysfunction and cognitive impairment. Vildagliptin and sitagliptin, dipeptidyl-peptidase-4 inhibitors, are recently developed anti-diabetic drugs. However, the effects of both drugs on cognitive behaviors and brain mitochondrial function in HFD-induced insulin-resistant rats have not yet been investigated. Sixty male Wistar rats were divided into two groups to receive either normal diet or HFD for 12 weeks. Rats in each group were then further divided into three treatment groups to receive either vehicle, vildagliptin (3 mg/kg per day), or sitagliptin (30 mg/kg per day) for 21 days. The cognitive behaviors of the rats were tested using the Morris Water Maze test. Blood samples were collected to determine metabolic parameters and plasma oxidative stress levels. Upon completion of the study, the animals were killed and the brains were removed to investigate brain and hippocampal mitochondrial function as well as to determine oxidative stress levels. We demonstrated that both drugs significantly improved the metabolic parameters and decreased circulating and brain oxidative stress levels in HFD-induced insulin-resistant rats. In addition, both drugs completely prevented brain and hippocampal mitochondrial dysfunction and equally improved the learning behaviors impaired by the HFD. Our findings suggest that the inhibition of dipeptidyl-peptidase-4 enzymes with vildagliptin or sitagliptin in insulin-resistant rats not only increases peripheral insulin sensitivity but also decreases brain dysfunction.
authors.affiliation: Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Hiranya
authors.initials: H
authors.lastname: Pintana
authors.forename: Nattayaporn
authors.initials: N
authors.lastname: Apaijai
authors.forename: Nipon
authors.initials: N
authors.lastname: Chattipakorn
authors.forename: Siriporn C
authors.initials: SC
authors.lastname: Chattipakorn
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003072:Cognition Disorders / Q000150:complications / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000150:complications / Q000517:prevention & control*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009570:Nitriles / Q000627:therapeutic use; D009765:Obesity / Q000150:complications / Q000209:etiology; D018384:Oxidative Stress / Q000187:drug effects; D011719:Pyrazines / Q000627:therapeutic use; D011759:Pyrrolidines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000627:therapeutic use; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011719:Pyrazines; D011759:Pyrrolidines; D014230:Triazoles; D000077597:Vildagliptin; D000218:Adamantane; D000068900:Sitagliptin Phosphate
keywords: DDP-4 inhibitors; brain mitochondrial dysfunction; high-fat diet; insulin resistance; memory decline