Abstract
Genistein, 4′,5,7-trihydroxyisoflavone, is a major isoflavone in soybean, which is known as phytestrogen having known benefit to brain functions. Being a common phytestrogen, the possible role of genistein in the brain protection needs to be further explored. In cultured PC12 cells, application of genistein significantly induced the expression of neurofilaments (NFs), markers for neuronal differentiation. In parallel, the expression of tetrameric form of proline-rich membrane anchor (PRiMA)-linked acetyl-cholinesterase (G4 AChE), a key enzyme to hydrolyze acetylcholine in cholinergic synapses, was induced in a dose-dependent manner: this induction included the associated protein PRiMA. The genistein-induced AChE expression was fully blocked by the pre-treatment of H89 (an inhibitor of protein kinase A, PKA) and G15 (a selective G protein-coupled receptor 30 (GPR30) antagonist), which suggested a direct involvement of a membrane-bound estrogen receptor (ER), named as GPR30 in the cultures. In parallel, the estrogen-induced activation of GPR30 induced AChE expression in a dose-dependent manner. The genistein/estrogen-induced AChE expression was triggered by a cyclic AMP responding element (CRE) located on the ACHE gene promoter. The binding of this CRE site by cAMP response element-binding protein (CREB) induced ACHE gene transcription. In parallel, increased expression levels of miR132 and miR212 were found when cultured PC12 cells were treated with genistein or G1. Thus, a balance between production and destruction of AChE by the activation of GPR30 was reported here. We have shown for the first time that the activation of GPR30 could be one way for estrogen or flavonoids, possessing estrogenic properties, to enhance cholinergic functions in the brain, which could be a good candidate for possible treatment of neurodegenerative diseases.
Highlights
Flavonoids are belonging to a family of polyphenolic compounds, which are considered as phytestrogen (Miksicek, 1993; Zhu et al, 2007)
The effect of genistein on the cell viability in PC12 cells was first determined by MTT assay
By compared to the negative control (DMSO treatment), genistein treatment at concentrations not more than 10 μM showed no significant effect on cell viability (Supplementary Figure S1), indicating that the current treatments were not cytotoxic to neuronal cells
Summary
Flavonoids are belonging to a family of polyphenolic compounds, which are considered as phytestrogen (Miksicek, 1993; Zhu et al, 2007). Flavonoids possess beneficial effects in a number of disease states, including neurodegenerative disorders, cancer and cardiovascular disease. The brain beneficial effects of flavonoids have been proposed in neuroprotection against neurotoxin stress, promotion of memory, learning and cognitive functions (Zhu et al, 2007, 2009; Choi et al, 2010). Flavonoids could be one of the resources in developing new drugs or food supplements for the prevention of neurodegenerative diseases, e.g., Alzheimer’s disease (AD) and depression. The low toxicity of flavonoids in human has been known (Miksicek, 1993)
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