Phytoestrogen alpha-zearalanol attenuate endoplasmic reticulum stress to against cultured rat hippocampal neurons apoptotic death induced by amyloid beta25-35.

OBJECTIVE: Our previous studies demonstrated both phytoestrogen α-zearalanol (α-ZAL) and estrogen is effective decrease Alzheimer's disease (AD)-like apoptotic neuron death, but α-ZAL showed significantly less side-effect on breast and endometrial tissue compared to estrogen, it suggested that α-ZAL can be used as a potential substitute for estrogen. However, the molecular mechanism by which α-ZAL prevents neuron damage remains unclear. Growing evidence suggests that endoplasmic reticulum (ER) stress plays an important role in the process of cell apoptosis in AD; in addition, our published data indicated that α-ZAL possessed the potential ability to stabilize ER function. We therefore hypothesized that ER-stress mechanism maybe involved in the antiapoptotic effect of α-ZAL in this study. METHODS: Primary rat hippocampal neurons have been cultured and subsequently followed exposed to ß-peptide fragment 25-35(Aß25-35) with or without α-ZAL pre-treatment, and then western blot and flow cytometry techniques has been used to evaluate the intracellular calcium balance, ER stress and apoptotic cell death. RESULTS: The results showed that Aß25-35 treatment for 24h induced dramatic neuronal apoptosis, accompanied by an increase in calpain2 expression, a marker of intracellular calcium overload. On the other hand, ER stress sensitive hallmarks, glucose-regulated protein 78 (GRP78), double-stranded RNA-dependent protein kinase (PKR)-like ER-resident kinase (PERK) and C/EBP homologous protein-10 (CHOP10) expressions were up-regulated after Aß25-35 administration. Importantly, α-ZAL pre-treatment effectively attenuated above changes. CONCLUSION: These results demonstrated that α-ZAL protects cells against AD-like apoptosis and the effects at least partially by attenuating severely ER stress.

Phytoestrogen α-zearalanol improves memory impairment and hippocampal neurogenesis in ovariectomized mice.

Estrogen is known to provide robust protection of memory in postmenopausal women, but the fact that estrogen may increase the incidence of uterine and breast tumors has undoubtedly limited the clinical use of estrogen. In the present study, the effect of α-zearalanol (α-ZAL), a plant-derived phytoestrogen with low side-effect on uterine and breast, on memory has been evaluated in ovariectomized (OVX) mice when using 17ß-estradiol (17ß-E2) as an estrogen positive control. Our findings demonstrated that OVX resulted in impaired spatial learning and memory and reduced numbers of newborn neurons in the dentate gyrus of the hippocampus, while 17ß-E2 or α-ZAL treatment significantly improved memory performance and restored hippocampal neurogenesis. We also found the reduction of brain derived neurotrophic factor (BDNF) and TrkB expression in OVX mice, which were ameliorated by 17ß-E2 or α-ZAL supplementation. These results indicated that α-ZAL may improve memory impairments induced by OVX and modulate the expression of BDNF-TrkB benefit to neurogenesis which may be involved in the memory protection from α-ZAL, in a manner similar to that of 17ß-E2. The present findings suggested that α-ZAL may be a plausible substitute of 17ß-E2 in improving memory in postmenopausal women.