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Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyoku, Kyoto 606-8507, Japan; and
* Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyoku, Kyoto 606-8501, Japan
1Correspondence: Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyoku, Kyoto 606-8507, Japan. E-mail: i53367{at}sakura.kudpc.kyoto-u.ac.jp
Parkinson’s disease is characterized by the mesencephalic dopaminergic
neuronal loss, possibly by apoptosis, and the prevalence is higher in
males than in females. The estrogen receptor (ER) subtype in the
mesencephalon is exclusively ER ß, a recently cloned novel subtype.
Bound with estradiol, it enhances gene transcription through the
estrogen response element (ERE) or inhibits it through the activator
protein-1 (AP-1) site. We demonstrated that 17ß-estradiol provided
protection against nigral neuronal apoptosis caused by exposure to
either bleomycin sulfate (BLM) or buthionine sulfoximine (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 blocked 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
caspase-3 activation and c-Jun NH2-terminal kinase (JNK),
which were activated by BLM. It also suppressed apoptosis by serum
deprivation, which was independent of caspase-3 activation. Therefore,
the antiapoptotic neuroprotection by estradiol is mediated by
transcription through AP-1 site downstream from JNK and caspase-3
activation. Furthermore, 17
-estradiol, a stereoisomer without female
hormone activity, also provided an antiapoptotic effect. Therefore, the
antiapoptotic effect is independent of female hormone
activity.—Sawada, H., Ibi, M., Kihara, T., Urushitani, M., Honda, K.,
Nakanishi, M., Akaike, A., Shimohama, S. Mechanisms of
antiapoptotic effects of estrogens in nigral dopaminergic neurons.
Key Words: estrogen receptor ß • AP-1 element • Parkinson’s disease • neuroprotection
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