Pioglitazone and exenatide enhance cognition and downregulate hippocampal beta amyloid oligomer and microglia expression in insulin-resistant rats

Can J Physiol Pharmacol. 2016 Aug;94(8):819-28. doi: 10.1139/cjpp-2015-0242. Epub 2015 Dec 16.


Insulin resistance is known to be a risk factor for cognitive impairment, most likely linked to insulin signaling, microglia overactivation, and beta amyloid (Aβ) deposition in the brain. Exenatide, a long lasting glucagon-like peptide-1 (GLP-1) analogue, enhances insulin signaling and shows neuroprotective properties. Pioglitazone, a peroxisome proliferated-activated receptor-γ (PPAR-γ) agonist, was previously reported to enhance cognition through its effect on Aβ accumulation and clearance. In the present study, insulin resistance was induced in male rats by drinking fructose for 12 weeks. The effect of monotherapy with pioglitazone (10 mg·kg(-1)) and exenatide or their combination on memory dysfunction was determined and some of the probable underlying mechanisms were studied. The current results confirmed that (1) feeding male rats with fructose syrup for 12 weeks resulted in a decline of learning and memory registered in eight-arm radial maze test; (2) treatment with pioglitazone or exenatide enhanced cognition, reduced hippocampal neurodegeneration, and reduced hippocampal microglia expression and beta amyloid oligomer deposition in a manner that is equal to monotherapies. These results may give promise for the use of pioglitazone or exenatide for ameliorating the learning and memory deficits associated with insulin resistance in clinical setting.

Keywords: cognitive impairment; déficit cognitif; exenatide; insulin-resistant rats; microglia; microglie; pioglitazone; rats insulino-résistants.

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Animals
  • Cognition / drug effects*
  • Cognition / physiology
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Drug Therapy, Combination
  • Exenatide
  • Fructose / administration & dosage
  • Fructose / toxicity
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Insulin Resistance* / physiology
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Memory Disorders / chemically induced
  • Memory Disorders / drug therapy
  • Memory Disorders / metabolism
  • Microglia / drug effects*
  • Microglia / metabolism
  • Nootropic Agents / pharmacology
  • Nootropic Agents / therapeutic use
  • PPAR gamma / agonists
  • Peptides / administration & dosage*
  • Pioglitazone
  • Rats
  • Rats, Wistar
  • Thiazolidinediones / administration & dosage*
  • Venoms / administration & dosage*


  • Amyloid beta-Peptides
  • Nootropic Agents
  • PPAR gamma
  • Peptides
  • Thiazolidinediones
  • Venoms
  • Fructose
  • Exenatide
  • Pioglitazone