title: Sitagliptin attenuated brain damage and cognitive impairment in mice with chronic cerebral hypo-perfusion through suppressing oxidative stress and inflammatory reaction.
abstract: BACKGROUND
  Sitagliptin, a new antidiabetic drug that inhibits dipeptidyl peptidase (DPP)-4 enzyme activity, has been reported to possess neuroprotective property. We tested the protective effects of sitagliptin against chronic cerebral hypoperfusion (CHP) in mice after bilateral carotid artery stenosis (BCAS).
  
  
  METHODS
  Thirty C57BL/6 mice were divided into three groups: sham control (n = 10), CHP (n = 10) and CHP-sitagliptin (orally 600 mg/kg/day) (n = 10). Working memory was assessed with novel-object recognition test. MRI was performed at day 0 and day 90 after BCAS procedure prior to sacrifice.
  
  
  RESULTS
  Immunohistochemical (IHC) staining showed significantly enhanced white matter lesions, microglia activation and astrocytosis of white matter in CHP group than in sham control, but the changes were significantly suppressed after sitagliptin treatment (all P < 0.01). The mRNA expressions of inflammatory [tumour necrosis factor-alpha (TNF-α), monocyte chemoattractant protein (MCP-1) and matrix metalloproteinase (MMP)-2] and apoptotic (Bax) biomarkers showed an identical pattern, whereas the anti-inflammatory (interleukin, IL-10) and antiapoptotic (Bcl-2) biomarkers showed an opposite pattern compared with that of IHC among all groups (all P < 0.01). The protein expressions of oxidative stress (NOX-I, NOX-II, nitrotyrosin, oxidized protein), inflammatory [nuclear factor-kappa B (NF-κB), TNF-α and MMP-2], apoptotic [mitochondrial Bax, cleaved poly(ADP-ribose) polymerase (PARP)] and DNA-damage (γ-H2AX) markers showed an identical pattern, while expression pattern of antiapoptotic marker (Bcl-2) was opposite to that of IHC (all P < 0.01). Glycogen-like peptide-1 receptor protein expression progressively increased from sham control to CHP-sitagliptin (P < 0.01). The short-term working-memory loss and MRI/diffusion tensor imaging (DTI) showed a pattern identical to that of IHC in all groups (all P < 0.01).
  
  
  CONCLUSIONS
  Sitagliptin protected against cognitive impairment and brain damage in a murine CHP model.
authors.affiliation: aDivision of Cardiology, Department of Internal Medicine bDepartment of Emergency Medicine, E-Da Hospital, I-Shou University cCenter for Translational Research in Biomedical Sciences dDepartment of Biological Sciences, National Sun Yat-Sen University eInstitute of Shock Wave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan *Indicates equal contribution by these authors.
authors.forename: Tzu-Hsien
authors.initials: TH
authors.lastname: Tsai
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.forename: Chai-Hao
authors.initials: CH
authors.lastname: Su
authors.forename: Pei-Hsun
authors.initials: PH
authors.lastname: Sung
authors.forename: Sarah
authors.initials: S
authors.lastname: Chua
authors.forename: Yen-Yi
authors.initials: YY
authors.lastname: Zhen
authors.forename: Steve
authors.initials: S
authors.lastname: Leu
authors.forename: Hsueh-Wen
authors.initials: HW
authors.lastname: Chang
authors.forename: Jenq-Lin
authors.initials: JL
authors.lastname: Yang
authors.forename: Hon-Kan
authors.initials: HK
authors.lastname: Yip
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D000068900:Sitagliptin Phosphate / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; C508609:IL10 protein, human; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D052216:Glucagon-Like Peptide 1; D000068900:Sitagliptin Phosphate