The prokineticin receptor antagonist PC1 rescues memory impairment induced by β amyloid administration through the modulation of prokineticin system

Neuropharmacology. 2019 Nov 1:158:107739. doi: 10.1016/j.neuropharm.2019.107739. Epub 2019 Aug 10.

Abstract

Growing evidences demonstrate that chemokines and chemokine receptors are up-regulated in resident central nervous system cells during Alzheimer's disease contributing to neuroinflammation and neurodegeneration. Prokineticin 2 belongs to a new family of chemokines which recently emerged as a critical player in immune system and inflammatory diseases. Since pharmacological blockade in vitro of the prokineticin system is able to antagonize Amyloid β-induced neurotoxicity, the aim of the present study was to investigate in vivo effects of prokineticin receptor antagonist PC1 on memory impairment in a rodent model of Alzheimer's disease. Rats were intracerebroventricular infused with Aβ1-42 and behavioral responses as well as the expression profile in hippocampus of prokineticin 2 and its receptors were investigated. Results demonstrated that Aβ1-42-infused rats developed significant memory impairments together with a marked up-regulation of both prokineticin 2 and its receptors in hippocampal neurons and astrocytes. Treatment with PC1 significantly improved learning capability of Aβ1-42-infused rats restoring the balance of prokineticin system. This study pointed to a neuroprotective role of PC1 on Aβ1-42-induced memory deficits that could be ascribed to the ability of PC1 to modulate rat hippocampal prokineticin system and to recover the impaired Aβ1-42-induced neurogenesis. This suggests that prokineticin system antagonism could be considered as a new approach for the study of AD etiopathology.

Keywords: Alzheimer's disease; Amyloid β; Animal model; Neurogenesis; Neuroprotection; Prokineticin 2; Prokineticin receptor antagonist; Prokineticin receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease*
  • Amyloid beta-Peptides / toxicity
  • Animals
  • Disease Models, Animal
  • Gastrointestinal Hormones / genetics
  • Gastrointestinal Hormones / metabolism
  • Gliosis
  • Guanidines / pharmacology
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Infusions, Intraventricular
  • Learning / drug effects*
  • Male
  • Maze Learning
  • Memory / drug effects
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism
  • Neurogenesis / drug effects
  • Neuropeptides / drug effects*
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Neuroprotective Agents / pharmacology*
  • Nitric Oxide Synthase Type II / drug effects
  • Nitric Oxide Synthase Type II / metabolism
  • Peptide Fragments / toxicity
  • Rats
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Peptide / antagonists & inhibitors*
  • Receptors, Peptide / genetics
  • Receptors, Peptide / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spatial Learning / drug effects
  • Triazines / pharmacology

Substances

  • Amyloid beta-Peptides
  • Gastrointestinal Hormones
  • Guanidines
  • NF-kappa B
  • Neuropeptides
  • Neuroprotective Agents
  • PROKR1 protein, rat
  • Peptide Fragments
  • Prok2 protein, rat
  • Receptors, G-Protein-Coupled
  • Receptors, Peptide
  • Triazines
  • amyloid beta-protein (1-42)
  • prokineticin receptor 2, rat
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat