Agmatine ameliorates type 2 diabetes induced-Alzheimer's disease-like alterations in high-fat diet-fed mice via reactivation of blunted insulin signalling

Neuropharmacology. 2017 Feb;113(Pt A):467-479. doi: 10.1016/j.neuropharm.2016.10.029. Epub 2016 Oct 31.

Abstract

The risk of Alzheimer's disease (AD) is higher in patients with type 2 diabetes mellitus (T2DM). Previous studies in high-fat diet-induced AD animal models have shown that brain insulin resistance in these animals leads to the accumulation of amyloid beta (Aβ) and the reduction in GSK-3β phosphorylation, which promotes tau phosphorylation to cause AD. No therapeutic treatments that target AD in T2DM patients have yet been discovered. Agmatine, a primary amine derived from l-arginine, has exhibited anti-diabetic effects in diabetic animals. The aim of this study was to investigate the ability of agmatine to treat AD induced by brain insulin resistance. ICR mice were fed a 60% high-fat diet for 12 weeks and received one injection of streptozotocin (100 mg/kg/ip) 4 weeks into the diet. After the 12-week diet, the mice were treated with agmatine (100 mg/kg/ip) for 2 weeks. Behaviour tests were conducted prior to sacrifice. Brain expression levels of the insulin signal molecules p-IRS-1, p-Akt, and p-GSK-3β and the accumulation of Aβ and p-tau were evaluated. Agmatine administration rescued the reduction in insulin signalling, which in turn reduced the accumulation of Aβ and p-tau in the brain. Furthermore, agmatine treatment also reduced cognitive decline. Agmatine attenuated the occurrence of AD in T2DM mice via the activation of the blunted insulin signal.

Keywords: Agmatine; Alzheimer's disease; Brain insulin resistance; High-fat diet.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agmatine / pharmacology
  • Agmatine / therapeutic use*
  • Alzheimer Disease / blood
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / etiology
  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Brain / drug effects
  • Brain / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / etiology
  • Diet, High-Fat / adverse effects*
  • Insulin / metabolism*
  • Insulin Resistance / physiology
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred ICR
  • Random Allocation

Substances

  • Blood Glucose
  • Insulin
  • Agmatine