Estradiol or genistein prevent Alzheimer's disease-associated inflammation correlating with an increase PPAR gamma expression in cultured astrocytes

Brain Res. 2010 Feb 2;1312:138-44. doi: 10.1016/j.brainres.2009.11.044. Epub 2009 Nov 27.

Abstract

Inflammation has been implicated in neurodegenerative disorders such as Alzheimer's disease (AD). The main inflammatory players in AD are the glial cells which initiate the inflammatory response. One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of A beta deposition. It is desirable to find methods of tipping the balance towards anti-inflammatory state. Estrogenic compounds have shown anti-inflammatory and also antioxidant activity. Astrocytes were pretreated with 17-beta estradiol or with genistein, and 48 h later treated with 5 microM amyloid beta (A beta) for 24 h. We found that A beta induces inflammatory mediators, such as cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha). All these effects were prevented when cells were pretreated with estradiol or genistein, demonstrating anti-inflammatory effects of estradiol or genistein in astrocytes in primary culture. The A beta-stimulated expression of pro-inflammatory genes in cells is antagonized by the action of the PPARs (peroxisome proliferator activated receptors). Here we detected an increase in PPAR-gamma expression in astrocytes in primary culture treated with A beta and estradiol or soy isoflavone genistein. Thus, some of the anti-inflammatory effects of estrogenic compounds may be mediated and activated by PPARs suppressing a diverse array of inflammatory responses caused by A beta in astrocytes in primary culture.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / toxicity
  • Animals
  • Astrocytes / drug effects*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cyclooxygenase 2 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme-Linked Immunosorbent Assay / methods
  • Estradiol / pharmacology*
  • Estrogens / pharmacology*
  • Gene Expression Regulation / drug effects*
  • Genistein / pharmacology*
  • Interleukin-1beta / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Peptide Fragments / toxicity
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Amyloid beta-Peptides
  • Estrogens
  • Interleukin-1beta
  • PPAR gamma
  • Peptide Fragments
  • Protein Kinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Estradiol
  • Genistein
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2