Effects of acute and chronic administration of GIP analogues on cognition, synaptic plasticity and neurogenesis in mice

Eur J Pharmacol. 2012 Jan 15;674(2-3):294-306. doi: 10.1016/j.ejphar.2011.11.007. Epub 2011 Nov 12.

Abstract

Type 2 diabetes is a risk factor for Alzheimer's disease. Insulin receptor desensitisation has been found in Alzheimer brains, which may be the underlying link. Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, normalises insulin signalling in diabetes. GIP and the GIP receptors are widely expressed in the brain, and GIP has been shown to have growth factor and neuroprotective properties. Here we investigate the potential therapeutic properties of different doses of the protease resistant long-lasting GIP receptor agonist D-Ala2GIP and the antagonist (Pro3)GIP in C57Bl/6 mice. We found that after acute injection, D-Ala2GIP had few effects on general behaviour in the open field at any dose tested (2.5, 25, 100, or 250 nmol/kg i.p.). In memory tests, no change was observed, whilst (Pro3)GIP at 25 nmol/kg i.p. impaired memory formation. In a chronic study over 4 weeks, mice injected with D-Ala2GIP (2.5 or 25 nmol/kg i.p.) and (Pro3)GIP (25 nmol/kg i.p.) learned a water maze task and object recognition task without impairment. In LTP recording in area CA1, both (Pro3)GIP as well as D-Ala2GIP enhanced LTP formation. In addition, the proliferation of neuronal progenitor cells in the dentate gyrus was increased both by D-Ala2GIP and (Pro3)GIP. The results show that the antagonist (Pro3)GIP has agonistic effects in chronic use, and both (Pro3)GIP and the agonist D-Ala2GIP are safe to use in wt mice and induces no major behavioural side effects nor impairments in learning whilst enhancing LTP and neuronal progenitor cell proliferation, which may be useful in treating neurodegenerative diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA1 Region, Hippocampal / cytology
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / physiology
  • Cell Proliferation / drug effects
  • Cognition / drug effects*
  • Dentate Gyrus / cytology
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / physiology
  • Exploratory Behavior / drug effects
  • Gastric Inhibitory Polypeptide / administration & dosage
  • Gastric Inhibitory Polypeptide / analogs & derivatives*
  • Gastric Inhibitory Polypeptide / pharmacology*
  • Long-Term Potentiation / drug effects
  • Male
  • Memory / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects
  • Neurogenesis / drug effects*
  • Neuronal Plasticity / drug effects*
  • Receptors, Gastrointestinal Hormone / agonists
  • Synapses / drug effects*
  • Synapses / metabolism
  • Time Factors

Substances

  • Receptors, Gastrointestinal Hormone
  • Gastric Inhibitory Polypeptide
  • gastric inhibitory polypeptide receptor