Impact of the selective estrogen receptor modulator, raloxifene, on neuronal survival and outgrowth following toxic insults associated with aging and Alzheimer's disease

Kathleen O'Neill, Shuhua Chen, Roberta Diaz Brinton

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

The current study investigated the estrogen agonist-antagonist properties of the selective estrogen receptor modulator, raloxifene (Ral), on neuroprotection and neuronal markers of memory function. Low concentrations of raloxifene significantly reduced basal markers of membrane damage and had no deleterious effect on neuronal survival. However, high concentrations of raloxifene (1000-5000 ng/ml) induced a significant increase in markers of membrane damage and a significant decrease in neuronal survival. At subtoxic concentrations, raloxifene induced significant neuroprotection against beta amyloid25-35-, hydrogen peroxide- and glutamate-induced toxicity. Results of analyses to determine whether raloxifene acted competitively or synergistically with 17 β-estradiol revealed that a postmenopausal level of 17 β-estradiol exerted a significantly greater increase in neuronal survival against beta-amyloid- and glutamate-induced toxicity compared to 50 ng/ml raloxifene. The combined presence of raloxifene and 17 β-estradiol was significantly neuroprotective against beta amyloid25-35- and glutamate-induced excitotoxicity but was significantly lower than 17 β-estradiol alone while not significantly different than raloxifene alone. Morphologic analyses demonstrated that raloxifene significantly increased neuronal outgrowth of hippocampal neurons within a narrow dose range that was blocked by a glutamate NMDA receptor antagonist. Raloxifene did not promote the outgrowth of basal forebrain or cortical neurons. Results of this study indicate that raloxifene exerted partial estrogen agonist action in the absence of 17 β-estradiol whereas in the presence of 17 β-estradiol, raloxifene exerted a mixed estrogen agonist-antagonist effect.

Original languageEnglish (US)
Pages (from-to)63-80
Number of pages18
JournalExperimental Neurology
Volume185
Issue number1
DOIs
StatePublished - Jan 2004
Externally publishedYes

Keywords

  • Basal forebrain
  • Beta amyloid
  • Cerebral cortex
  • Estrogen agonist
  • Estrogen antagonist
  • Hippocampus
  • Neuroprotection
  • Neurotrophism
  • Raloxifene
  • SERM

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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