Department of Molecular
Pharmacology and Toxicology and the Program in Neuroscience,
University of Southern California, Pharmaceutical
Sciences Center, 1985 Zonal Avenue, Los Angeles, CA
90033, USA.
The current study investigated the
neurotrophic and neuroprotective action of the complex
formulation of conjugated equine Estrogens (CEEs),
the most frequently prescribed estrogen replacement
therapy in the United States and the estrogen replacement
therapy of the Women's Health Initiative. Morphologic
analyses demonstrated that CEEs significantly increased
neuronal outgrowth in hippocampal, basal forebrain,
occipital, parietal and frontal cortex neurons. Dose-response
analyses indicated that the lowest effective concentration
of CEEs exerted the maximal neurotrophic effect with
greatest potency occurring in hippocampal and occipital
cortex neurons. CEES induced highly significant neuroprotection
against beta amyloid(25-35), hydrogen peroxide and
glutamate-induced toxicity. Rank order of potency
and magnitude of CEE-induced neuroprotection in the
brain regions investigated was hippocampal neurons
> basal forebrain neurons > cortical neurons.
In hippocampal neurons pre-exposed to beta amyloid(25-35),
CEEs halted Abeta(25-35)-induced cell death and protected
surviving neurons from further cell death induced
by Abeta(25-35). Because CEEs are the estrogen replacement
therapy of the Women's Health Initiative, results
of the current study could provide cellular mechanisms
for understanding effects of CEEs on cognitive function
and risk of Alzheimer's disease derived from this
prospective clinical trial.