TY - JOUR
T1 - Role of nonfeminizing estrogens in brain protection from cerebral ischemia
T2 - An animal model of Alzheimer's disease neuropathology
AU - Simpkins, James W.
AU - Wen, Yi
AU - Perez, Evelyn
AU - Yang, Shaohua
AU - Wang, Xiaofei
PY - 2005
Y1 - 2005
N2 - Estrogens are potent and efficacious neuroprotectants both in vitro and in vivo in a variety of models of neurotoxicity. We determined the structural requirements for neuroprotection in in vitro assays using a library of more than 70 novel estratrienes, synthesized to reduce or eliminate estrogen receptor (ER) binding. We observed that neuroprotection could be enhanced by as much as 200-fold through modifications that positioned a large, balky group at the C2 and/or C4 position of the phenolic A ring of the estratriene. Further, substitutions on the B, C, or D rings either reduced or did not markedly change neuroprotection. For this library of compounds, there was a negative correlation between ER binding and neuroprotection, as the more potent compounds showed weaker or no ER binding. In an in vivo model for neuroprotection, transient cerebral ischemia, efficacious compounds were active in protection of brain tissue from this pro-oxidant insult. Finally, estradiol protected brains from insult-induced Alzheimer's disease (AD) neuropathology, including activation of apoptosis, stimulation of Aβ production, hyperphosphorylation of tau, activation of cyclin-dependent kinases, and activation of catastrophic attempts at neuronal mitosis. Collectively, these results demonstrate that nonfeminizing estrogens are neuroprotective and protect the brain from the induction of AD-like neuropathology in an animal model. These features of nonfeminizing estrogens make them attractive compounds for assessment of efficacy in AD and stroke, because they are not expected to show the side effects of chronic estrogen therapy that are ER mediated in the liver, uterus, and breast.
AB - Estrogens are potent and efficacious neuroprotectants both in vitro and in vivo in a variety of models of neurotoxicity. We determined the structural requirements for neuroprotection in in vitro assays using a library of more than 70 novel estratrienes, synthesized to reduce or eliminate estrogen receptor (ER) binding. We observed that neuroprotection could be enhanced by as much as 200-fold through modifications that positioned a large, balky group at the C2 and/or C4 position of the phenolic A ring of the estratriene. Further, substitutions on the B, C, or D rings either reduced or did not markedly change neuroprotection. For this library of compounds, there was a negative correlation between ER binding and neuroprotection, as the more potent compounds showed weaker or no ER binding. In an in vivo model for neuroprotection, transient cerebral ischemia, efficacious compounds were active in protection of brain tissue from this pro-oxidant insult. Finally, estradiol protected brains from insult-induced Alzheimer's disease (AD) neuropathology, including activation of apoptosis, stimulation of Aβ production, hyperphosphorylation of tau, activation of cyclin-dependent kinases, and activation of catastrophic attempts at neuronal mitosis. Collectively, these results demonstrate that nonfeminizing estrogens are neuroprotective and protect the brain from the induction of AD-like neuropathology in an animal model. These features of nonfeminizing estrogens make them attractive compounds for assessment of efficacy in AD and stroke, because they are not expected to show the side effects of chronic estrogen therapy that are ER mediated in the liver, uterus, and breast.
KW - Alzheimer's disease
KW - Estrogens
KW - Neuroffibrillary tangles
KW - Neuroprotection
KW - Stroke
UR - http://www.scopus.com/inward/record.url?scp=25144462015&partnerID=8YFLogxK
U2 - 10.1196/annals.1347.019
DO - 10.1196/annals.1347.019
M3 - Article
C2 - 16024766
AN - SCOPUS:25144462015
SN - 0077-8923
VL - 1052
SP - 233
EP - 242
JO - Annals of the New York Academy of Sciences
JF - Annals of the New York Academy of Sciences
ER -