title: DPP-4 inhibition with linagliptin ameliorates cognitive impairment and brain atrophy induced by transient cerebral ischemia in type 2 diabetic mice.
abstract: BACKGROUND
  It is unclear whether dipeptidylpeptidase-4 (DPP-4) inhibition can counteract the impairment of cognitive function and brain injury caused by transient cerebral ischemia in type 2 diabetes. The present study was undertaken to test our hypothesis that linagliptin, a DPP-4 inhibitor, administration following transient cerebral ischemia can ameliorate cognitive impairment and brain injury in diabetic mice.
  
  
  METHODS
  db/db mice, a model of obese type 2 diabetes, were subjected to transient cerebral ischemia by 17 min of bilateral common carotid artery occlusion (BCCAO), and were administered (1) vehicle or (2) linagliptin for 8 weeks or 1 week. For the long-term experiment on 8 weeks of linagliptin treatment, cognitive function, and volume and neuronal cell number of hippocampus and cortex were estimated in each group of mice. For the short-term experiment on 1 week of linagliptin treatment, cerebral IgG extravasation, Iba-1 positive cell number (reactive microglia), oxidative stress, and claudin-5 and gp91phox protein levels were measured in each group of mice.
  
  
  RESULTS
  Linagliptin administration almost completely suppressed the circulating DPP-4 activity in db/db mice, but did not significantly reduce blood glucose or ameliorate glucose intolerance in db/db mice. Linagliptin administration following transient cerebral ischemia significantly counteracted cognitive impairment in diabetic mice, as estimated by water maze test and passive avoidance test. Linagliptin administration ameliorated the decrease in cerebral volume and neuronal cell number in hippocampus and cortex of diabetic mice. Linagliptin administration significantly reduced the increase in cerebral IgG extravasation and the increase in reactive microglia caused by transient cerebral ischemia in diabetic mice. Furthermore, linagliptin significantly suppressed the increase in cerebral oxidative stress in transient cerebral ischemia-subjected diabetic mice. Furthermore, linagliptin significantly increased cerebral claudin-5 and significantly decreased gp91phox in diabetic mice subjected to transient cerebral ischemia.
  
  
  CONCLUSIONS
  DPP-4 inhibition with linagliptin counteracted cognitive impairment and brain atrophy induced by transient cerebral ischemia in diabetic mice, independently of blood glucose lowering effect. This cerebroprotective effect of linagliptin was associated with the suppression of blood-brain barrier disruption and the attenuation of cerebral oxidative stress. Thus, our present work highlights DPP-4 inhibition as a promising therapeutic strategy for cognitive impairment and cerebral vascular complications in type 2 diabetes.
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. 54494424@qq.com.
authors.forename: MingJie
authors.initials: M
authors.lastname: Ma
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. fpmhasse@yahoo.co.jp.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. koibuchi-circ@umin.ac.jp.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Koibuchi
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. ktoyama@stanford.edu.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Toyama
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. kenuekawa@gmail.com.
authors.forename: Ken
authors.initials: K
authors.lastname: Uekawa
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. 113r5133@st.kumamoto-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. parkmoon1982@yahoo.co.jp.
authors.forename: Bowen
authors.initials: B
authors.lastname: Lin
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. mitsuyam@gpo.kumamoto-u.ac.jp.
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
mesh_terms: D000818:Animals; D001284:Atrophy / Q000209:etiology; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D017536:Carotid Artery, Common; D002540:Cerebral Cortex / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000209:etiology; D003924:Diabetes Mellitus, Type 2; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007074:Immunoglobulin G / Q000187:drug effects / Q000276:immunology; D002546:Ischemic Attack, Transient / Q000150:complications / Q000276:immunology; D000069476:Linagliptin / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000276:immunology; D009929:Organ Size
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007074:Immunoglobulin G; D000069476:Linagliptin