Improvement in inflammation is associated with the protective effect of Gly-Pro-Glu and cycloprolylglycine against Aβ-induced depletion of the hippocampal somatostatinergic system

Neuropharmacology. 2019 Jun:151:112-126. doi: 10.1016/j.neuropharm.2019.04.008. Epub 2019 Apr 11.

Abstract

Glycine-proline-glutamate (GPE) is a cleaved tripeptide of IGF-I that can be processed to cycloprolylglycine (cPG) in the brain. IGF-I protects the hippocampal somatostatinergic system from β-amyloid (Aβ) insult and although neither IGF-I-derived peptides bind to IGF-I receptors, they exert protective actions in several neurological disorders. As their effects on the hippocampal somatostatinergic system remain unknown, the objective of this study was to evaluate if cPG and/or GPE prevent the deleterious effects of Aβ25-35 infusion on this system and whether changes in intracellular-related signaling and interleukin (IL) content are involved in their protective effect. We also determined the effect of cPG or GPE co-administration with Aβ25-35 on IL secretion in glial cultures and the influence of these ILs on signaling activation and somatostatin synthesis in neuronal cultures. cPG or GPE co-administration reduced Aβ-induced cell death and pro-inflammatory ILs, increased IL-4 and partially avoided the reduction of components of the somatostatinergic system affected by Aβ25-35. GPE increased activation of Akt and CREB and reduced GSK3β activation and astrogliosis, whereas cPG increased phosphorylation of extracellular signal-regulated kinases. Both peptides converged in the activation of mTOR and S6 kinase. Co-administration of these peptides with Aβ25-35 to glial cultures increased IL-4 and reduced IL-1β; this release of IL-4 could be responsible for activation of Akt and increased somatostatin in neuronal cultures. Our findings suggest that cPG and GPE exert protective effects against Aβ on the somatostatinergic system by a reduction of the inflammatory environment that may activate different pro-survival pathways in these neurons.

Keywords: Cycloprolylglycine; GPE; Hippocampus; Inflammation; Somatostatin; β-amyloid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / pharmacology*
  • Animals
  • Cell Death / drug effects
  • Female
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Oligopeptides / pharmacology
  • Oligopeptides / therapeutic use*
  • Peptide Fragments / pharmacology*
  • Peptides, Cyclic / pharmacology
  • Peptides, Cyclic / therapeutic use*
  • Phosphorylation / drug effects
  • Rats
  • Rats, Wistar
  • Receptors, Somatostatin / metabolism
  • Signal Transduction / drug effects
  • Somatostatin / metabolism*

Substances

  • Amyloid beta-Peptides
  • Neuroprotective Agents
  • Oligopeptides
  • Peptide Fragments
  • Peptides, Cyclic
  • Receptors, Somatostatin
  • Somatostatin
  • cyclo(prolylglycyl)
  • glycyl-prolyl-glutamic acid