Role of nuclear receptor on regulation of BDNF and neuroinflammation in hippocampus of β-amyloid animal model of Alzheimer's disease

Neurotox Res. 2014 May;25(4):335-47. doi: 10.1007/s12640-013-9437-9. Epub 2013 Nov 26.

Abstract

Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have been reported to provide neuroprotective effects against neurodegenerative diseases. The current study was carried out to investigate the effects of chronic administration of pioglitazone, a PPAR-γ agonist, on cognitive impairment in an animal model of Alzheimer's disease induced by β-amyloid. Wistar rats received intracerebroventricular (ICV) β-amyloid (βA) application (3 nmol/3 μL), and behavioral alterations (locomotor activity and memory performance) were assessed. Animals were sacrificed immediately following the last behavioral session, and their brains were removed and dissected. Mitochondrial enzymes, oxidative parameters, inflammatory mediators (TNF-α, IL-6), caspase activity, and BDNF levels were measured in the hippocampus. ICV βA-treated rats showed a memory deficit and significantly decreased BDNF level, simultaneously, increase in mitochondrial oxidative damage and inflammatory mediators in the hippocampus. Memory impairment and oxidative damage were reversed by administration of pioglitazone (15 and 30 mg/kg). Pioglitazone also significantly restored the BDNF level and attenuated the actions of inflammatory markers in ICV βA-treated rats. However, pretreatment with PPAR-γ antagonist BADGE (15 mg/kg) with higher dose of pioglitazone significantly reversed its protective action in memory impairment in βA-treated rats, which indicates the involvement of PPAR-γ receptors mediating neuroprotective action. These results demonstrate that pioglitazone offers protection against β-amyloid-induced memory dysfunction possibly due to its antioxidant, anti-inflammatory, anti-apoptotic action and neurogenesis-like effect therefore, could have a therapeutic potential in Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / immunology
  • Amyloid beta-Peptides
  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Cognition Disorders / drug therapy
  • Cognition Disorders / etiology
  • Cognition Disorders / immunology
  • Disease Models, Animal
  • Hippocampus / drug effects*
  • Hippocampus / immunology
  • Maze Learning / drug effects
  • Memory Disorders / drug therapy
  • Memory Disorders / etiology
  • Memory Disorders / immunology
  • Motor Activity / drug effects
  • Neuroprotective Agents / pharmacology*
  • PPAR gamma / agonists
  • Peptide Fragments
  • Pioglitazone
  • Rats, Wistar
  • Space Perception / drug effects
  • Thiazolidinediones / pharmacology*
  • Time Factors
  • Treatment Outcome

Substances

  • Amyloid beta-Peptides
  • Brain-Derived Neurotrophic Factor
  • Neuroprotective Agents
  • PPAR gamma
  • Peptide Fragments
  • Thiazolidinediones
  • amyloid beta-protein (1-42)
  • Pioglitazone