Unifying Mechanism of Estrogen-Induced Neuroprotection
Roberta Diaz Brinton and Jon Nilsen
Department of Molecular Pharmacology and Toxicology, and Neuroscience,
University of Southern California, Pharmaceutical Sciences, 1985 Zonal
Avenue, Los Angeles, CA 90089
The ability of estrogen to protect against a wide range of neurotoxic
insults leads to the obvious question; How does one class of molecule
induce protection against a broad array of toxicants? Either estrogen
induces a myriad of protective mechanisms or estrogen induces a
unifying protective mechanism that promotes survival in the face of
multiple mechanistic toxicants. We tested the hypothesis that estrogen
induces a unifying mechanism of neuronal defense that would confer
protection against a broad array of mechanistically different
neurotoxicants. To address this hypothesis, we investigated the
estrogen-induced signaling cascade in cultured hippocampal neurons as a
model system. Results of these analyses indicate that 17 b-estradiol
activates a Src / MAPK signaling cascade that leads to activation of
the MAP kinases ERK1 / ERK2. We further found that 17 b-estradiol leads
to translocation of phospho-ERK1/ERK2 into the nucleus and activation
of the transcription factor CREB. 17 b-estradiol increased expression
of the antiapoptotic protein Bcl-2 in a MAPK dependent manner. Because
Bcl-2 can increase mitochondrial calcium load tolerance, we
investigated whether 17 b-estradiol would increase mitochondrial
calcium sequestration. Results of those studies indicate that 17
b-estradiol increases mitochondrial calcium sequestration under
excitotoxic glutamate conditions. Together these data suggest the
possibility that by increasing mitochondrial calcium sequestration and
calcium load tolerance, 17 b-estradiol induces a mechanism whereby
neurons are protected against neurodegenerative factors whose mechanism
of action is dysregulation of intracellular calcium levels. Such a
cascade would provide a unifying mechanism of neuroprotection against
factors that lead to calcium dysregulation in neurons. This research
is supported by the National Institutes of Aging, the Norris
Foundation, the Whittier Foundation and the Alzheimer's Association.
Key words:
Problems or questions regarding this site should be directed to
webmaster@americanaging.org