Parkinson's disease is characterized by the mesencephalic dopaminergic neur
onal loss, possibly by apoptosis, and the prevalence is higher in males tha
n in females. The estrogen receptor (ER) subtype in the mesencephalon is ex
clusively ER beta, a recently cloned novel subtype. Bound with estradiol, i
t enhances gene transcription through the estrogen response element (ERE) o
r inhibits it through the activator protein-1 (AP-1) site. We demonstrated
that 17 beta-estradiol provided protection against nigral neuronal apoptosi
s caused by exposure to either bleomycin sulfate (BLM) or buthionine sulfox
imine (BSO). BLM and BSO-induced nigral apoptosis was blocked by inhibitors
for caspase-3 or c-Jun/AP-1. The antiapoptotic effect by estradiol was blo
cked by ICI 182,780, an antagonist for ER, but not by a synthesized peptide
that inhibits binding of the ER to the ERE. Estradiol had no effects on ca
spase-3 activation and c-Jun NH2-terminal kinase (JNK), which were activate
d by BLM. It also suppressed apoptosis by serum deprivation, which was inde
pendent of caspase-3 activation. Therefore, the antiapoptotic neuroprotecti
on by estradiol is mediated by transcription through AP-1 site downstream f
rom JNK and caspase-3 activation. Furthermore, 17 alpha-estradiol, a stereo
isomer without female hormone activity, also provided an antiapoptotic effe
ct. Therefore, the antiapoptotic effect is independent of female hormone ac
tivity.-Sawada, H., Ibi, M., Kihara, T., Urushitani, M., Honda, K, Nakanish
i, M., Akaike, A., Shimohama, S. Mechanisms of antiapoptotic effects of est
rogens in nigral dopaminergic neurons.