17β-Estradiol Protects Neural Stem/Progenitor Cells Against Ketamine-Induced Injury Through Estrogen Receptor β Pathway

Abstract

Ketamine inhibits neural stem/progenitor cell (NSPC) proliferation and disrupts normal neurogenesis in the developing brain. 17β-Estradiol alleviates neurogenesis damage and enhances behavioral performance after ketamine administration. However, the receptor pathway of 17β-estradiol that protects NSPCs from ketamine-induced injury remains unknown. In the present study, we investigated the role of estrogen receptor α (ER-α) and estrogen receptor β (ER-β) in 17β-estradiol's protection against ketamine-exposed NSPCs and explored its potential mechanism. The primary cultured NSPCs were identified by immunofluorescence and then treated with ketamine and varying doses of ER-α agonist 4,4 ,4-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) or ER-β agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) for 24 h. NSPC proliferation was analyzed by 5-bromo-2-deoxyuridine incorporation test. The expression of phosphorylated glycogen synthase kinase-3β (p-GSK-3β) was quantified by western blotting. It was found that treatment with different concentrations of PPT did not alter the inhibition of ketamine on NSPC proliferation. However, treatment with DPN attenuated the inhibition of ketamine on NSPC proliferation at 24 h after their exposure (P < 0.05). Furthermore, treatment with DPN increased p-GSK-3β expression in NSPCs exposed to ketamine. These findings indicated that ER-β mediates probably the protective effects of 17β-estradiol on ketamine-damaged NSPC proliferation and GSK-3β is involved in this process

The Effects of Extrinsic and Intrinsic Factors on Neurogenesis

“…Estradiol also promotes cell proliferation and inhibits cell death in the SGZ by modulating the activity of estrogen receptors [236]. Studies have shown that treatment with exogenous estradiol inhibits the decrease in NSC neurogenesis, increase in cell death and impairment of cognition induced by exposure to ketamine by modulating the estrogen receptor β pathway associated with GSK-3β [240,241]. In addition, high exogenous and endogenous estradiol levels may increase the dendritic spine density in CA1 hippocampal pyramidal neurons, and dendritic morphology is regulated in a manner dependent on the concentration of estradiol [242,243].…”

Neurogenesis Potential Evaluation and Transcriptome Analysis of Fetal Hypothalamic Neural Stem/Progenitor Cells With Prenatal High Estradiol Exposure

“…Several published studies show that estrogen stimulates both proliferation and differentiation of NSC/NPCs (Okada et al, 2010;Li et al, 2020) and attenuates damage to neurogenesis in the developing brain caused by chemical drug exposure (Li et al, 2019); however, another study shows that 10 nM estradiol increases NSC/NPCs proliferation and stimulates differentiation into neurons in vitro, but 50 nM estradiol markedly decreases NSC/NPCs proliferation (Zhang et al, 2019a). Thus, the effects of maternal estradiol on neurogenesis of fetal hypothalamic NSC/NPCs may be dose dependent, and the dose that caused metabolic disorder in our mouse model exerted a different effect on proliferation and differentiation.…”

Targeting 17β-estradiol biosynthesis in neural stem cells improves stroke outcome

“…However, increasing evidence suggests we need to increase the therapeutic efficacy of the transplanted cells to enhance stroke recovery (Hermann et al, 2014;Damian et al, 2021). These improvements may be achieved by manipulating17β-estradiol (Liang et al, 2016;Li et al, 2020;Mihai et al, 2021). 17β-estradiol has beneficial effects on various stem cells and progenitor cells in improving recovery after myocardial ischemia (Yuan et al, 2018) and cerebral ischemia (Liang et al, 2016).…”