Mechanisms of antiapoptotic effects of estrogens in nigral dopaminergic neurons

Citation
H. Sawada et al., Mechanisms of antiapoptotic effects of estrogens in nigral dopaminergic neurons, FASEB J, 14(9), 2000, pp. 1202-1214
Citations number
73
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Experimental Biology
Journal title
FASEB JOURNAL
ISSN journal
0892-6638 → ACNP
Volume
14
Issue
9
Year of publication
2000
Pages
1202 - 1214
Database
ISI
SICI code
0892-6638(200006)14:9<1202:MOAEOE>2.0.ZU;2-0
Abstract
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.