title: PPARγ agonist pioglitazone reverses memory impairment and biochemical changes in a mouse model of type 2 diabetes mellitus.
abstract: OBJECTIVE
  Pioglitazone, known as a peroxisome proliferator-activated receptor γ (PPARγ) agonist, is used to treat type 2 diabetes mellitus (T2DM). T2DM has been associated with reduced performance on numerous domains of cognitive function. Here, we investigated the effects of pioglitazone on memory impairment in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice.
  
  
  METHODS
  ICR mice were fed with HFD for 4 weeks and then injected with a single low dose of STZ followed by continued HFD feeding for an additional 4 weeks. Pioglitazone (18 mg/kg, 9 mg/kg body weight) was orally administered for 6 weeks once daily. Y-maze test and Morris water maze test (MWM) were employed for testing learning and memory. Serum glucose, serum insulin, serum triglyceride, brain β-amyloid peptide (Aβ), brain β-site amyloid precursor protein cleaving enzyme (BACE1), brain nuclear factor κB (NF-κB), and brain receptor for advanced glycation end products (RAGE) were also tested.
  
  
  RESULTS
  The STZ/HFD diabetic mice, characterized by hyperglycemia, hyperlipemia and hypoinsulinemia, performed poorly on Y-maze and MWM hence reflecting impairment of learning and memory behavior with increases of Aβ40/Aβ42, BACE1, NF-κB, and RAGE in brain. Treatment of PPARγ agonist, pioglitazone (18 or 9 mg/kg body weight), significantly reversed diabetes-induced impairment of learning and memory behavior, which is involved in decreases of Aβ40/Aβ42 via inhibition of NF-κB, BACE1 and RAGE in brain as well as attenuation of hyperglycemia, hyperlipemia, and hypoinsulinemia.
  
  
  CONCLUSIONS
  It is concluded that PPARγ agonist pioglitazone may be considered as potential pharmacological agents for the management of cognitive dysfunction in T2DM.
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, China Department of Pharmacy, the Second Hospital Affiliated to Anhui Medical University, Hefei, China.
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Jiang
authors.forename: Su-Su
authors.initials: SS
authors.lastname: Tang
authors.forename: Xiao-Yun
authors.initials: XY
authors.lastname: Wang
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.forename: Mei
authors.initials: M
authors.lastname: Hu
authors.forename: Ming-Xing
authors.initials: MX
authors.lastname: Liao
authors.forename: Qi-Long
authors.initials: QL
authors.lastname: Ding
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Jia-Chang
authors.initials: JC
authors.lastname: Li
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000523:psychology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000523:psychology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000523:psychology*; D004797:Enzyme-Linked Immunosorbent Assay; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology*; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood
chemical_list: D016229:Amyloid beta-Peptides; D001786:Blood Glucose; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D007328:Insulin; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D000077205:Pioglitazone