Oestradiol or genistein rescues neurons from amyloid beta-induced cell death by inhibiting activation of p38.
Oestrogenic compounds have been postulated as neuroprotective agents. This prompted us to investigate their mechanism action in neurons in primary culture. Cells were pretreated with physiological concentrations of 17-beta estradiol (0.2 nm) or with nutritionally relevant concentrations of genistein (0.5 microm), and 48 h later treated with 5 microm of amyloid beta (Abeta) for 24 h. We found that Abeta increased oxidative stress, measured as peroxide levels or oxidized glutathione/reduced glutathione ratio, which in turn, caused phosphorylation of p38 MAP kinase. Amyloid beta subsequently induced neuronal death. Inhibiting the MAP kinase pathway prevented cell death, confirming the role of p38 in the toxic effect of Abeta. All these effects were prevented when cells were pretreated for 48 h with oestradiol or genistein. Therefore, oestrogenic compounds rescue neurons from Abeta-induced cell death by preventing oxidative stress, which in turn inhibits the activation of p38, protecting neurons from cell death. Because hormone replacement therapy with oestradiol could cause serious setbacks, the potential therapeutic effect of phyto-oestrogens for the prevention of Abeta-associated neurodegenerative disorders should be more carefully studied in clinical research.
Vallés
Soraya L
SL
Department of Physiology, University of Valencia, School of Medicine, Valencia, Spain.
Borrás
Consuelo
C
Gambini
Juan
J
Furriol
Jessica
J
Ortega
Angel
A
Sastre
Juan
J
Pallardó
Federico V
FV
Viña
Jose
J
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology*; D066298:In Vitro Techniques; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress; D048789:Phytoestrogens / Q000494:pharmacology*; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D004967:Estrogens; D048789:Phytoestrogens; D004958:Estradiol; D019833:Genistein; D048051:p38 Mitogen-Activated Protein Kinases