Estradiol protects dopaminergic neurons in a MPP+Parkinson's disease model.
The prevalence of Parkinson's disease is higher in males than in females. Although the reason for this gender difference is not clear, the level of female steroid hormones or their receptors may be involved in the pathogenesis. The estrogen receptor subtype expressed in the midbrain is limited to the novel beta subtype, whose role in the central nervous system has not been resolved. We demonstrated that ligand-activated estrogen receptor beta suppressed dopaminergic neuronal death in an in vitro Parkinson's disease model which uses 1-methyl-4-phenylpyridinium ions (MPP(+)). MPP(+) treatment caused the upregulation of c-Jun amino-terminal kinase (JNK) and dopaminergic neuronal death, the latter being blocked by curcumin, an inhibitor of the c-Jun/AP-1 cascade. 17alpha- and 17beta-estradiol both protected dopaminergic neurons from MPP(+)-induced neuronal death and this was blocked by a pure antagonist of the estrogen receptor, ICI 182,780, but not by an inhibitor of estrogen receptor dimerization, YP537. These data indicated that the neuroprotection provided by 17alpha-estradiol was via inhibitory transcriptional regulation at the activator protein-1 (AP-1) site mediated by estrogen receptor beta. Thus, 17alpha-estradiol is a suitable candidate for neuroprotective therapy of Parkinson's disease because it is associated with few undesirable feminizing effects.
Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyoku, Kyoto 606-8507, Japan.
Hideyuki
H
Sawada
Masakazu
M
Ibi
Takeshi
T
Kihara
Kazuhiro
K
Honda
Tomoki
T
Nakamizo
Rie
R
Kanki
Miki
M
Nakanishi
Noriko
N
Sakka
Akinori
A
Akaike
Shun
S
Shimohama
D015655:1-Methyl-4-phenylpyridinium / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004622:Embryo, Mammalian; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use*; D047629:Estrogen Receptor beta; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D011247:Pregnancy; D051381:Rats; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; D004958:Estradiol; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine