Genistein inhibits glutamate-induced apoptotic processes in primary neuronal cell cultures: An involvement of aryl hydrocarbon receptor and estrogen receptor/glycogen synthase kinase-3β intracellular signaling pathway

Abstract Phytoestrogens prevent neuronal damage, however, mechanism of their neuroprotective action has not been fully elucidated. This study aimed to evaluate the effects of genistein on glutamate-induced apoptosis in mouse primary neuronal cell cultures. Glutamate (1 mM) enhanced caspase-3 activit...

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Bibliographic Details
Published in:Neuroscience 2007-03, Vol.145 (2), p.592-604
Main Authors: Kajta, M, Domin, H, Grynkiewicz, G, Lason, W
Format: Article
Language:English
Subjects:
apoptosis
Biological and medical sciences
brain tissues
excitotoxicity
Fundamental and applied biological sciences. Psychology
Neurology
phytoestrogen
SERM
Vertebrates: nervous system and sense organs
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Summary:Abstract Phytoestrogens prevent neuronal damage, however, mechanism of their neuroprotective action has not been fully elucidated. This study aimed to evaluate the effects of genistein on glutamate-induced apoptosis in mouse primary neuronal cell cultures. Glutamate (1 mM) enhanced caspase-3 activity and lactate dehydrogenase (LDH) release in the hippocampal, neocortical and cerebellar neurons in time-dependent manner, and these data were confirmed at the cellular level with Hoechst 33342 and calcein AM staining. Genistein (10–10,000 nM) significantly inhibited glutamate-induced apoptosis, and the effect of this isoflavone was most prominent in the hippocampal cells. Next, we studied an involvement of estrogen and aryl hydrocarbon receptors in anti-apoptotic effects of genistein. A high-affinity estrogen receptor antagonist, ICI 182, 780 (1 μM), reversed, whereas less specific antagonist/partial agonist, tamoxifen (1 μM), either intensified or partially inhibited genistein effects. Aryl hydrocarbon receptor antagonist, α-naphthoflavone (1 μM), exhibited a biphasic action: it enhanced genistein action toward a short-term exposure (3 h) to glutamate, but antagonized genistein action toward prolonged exposure (24 h) to that insult. SB 216763 (1 μM), which preferentially inhibits glycogen synthase kinase-3β (GSK-3β), potentiated genistein effects. These data point to strong effects of genistein at low micromolar concentrations in various brain tissues against glutamate-evoked apoptosis. Moreover, this study provided evidence for involvement of aryl hydrocarbon receptor and estrogen receptor/GSK-3β intracellular signaling pathway in anti-apoptotic action of genistein.
ISSN:0306-4522
1873-7544
DOI:10.1016/j.neuroscience.2006.11.059