Protective effects of butein on corticosterone-induced cytotoxicity in Neuro2A cells

Masanori Ohmoto,Yukina Shibuya,Shihori Taniguchi,Tomoki Nakade,Masaaki Nomura,Yuri Ikeda-Matsuo,Tohru Daikoku

doi:10.1016/j.ibror.2020.02.002

Abstract

A functional understanding of the relationship between glucocorticoids and neuronal apoptosis induced by the production of reactive oxygen species (ROS) may lead to a novel strategy for the treatment or prevention of depression. Previous reports suggest that butein, a type of flavonoids, may be a potent candidate against depression-related neuronal cell apoptosis caused by oxidative stress; however, the protective effects of butein on damaged corticosterone (CORT)-treated neuronal cells has not been elucidated. In the present study, we examined the protective effect of butein on CORT-induced cytotoxicity and neurite growth during cell differentiation of mouse neuroblastoma Neuro2A (N2A) cells. Moreover, the effect on cultured cells by high concentrations of butein was confirmed. Our results demonstrate that CORT treatment significantly decreases cell viability and induces cell death. CORT was suggested to induce apoptosis via mitochondrial dysfunction and caspase-3 activation; this apoptosis may be attributed to DNA damage by ROS generation, found in this study to be significantly inhibited by pretreatment with butein. We found that CORT produced significant growth suppression of retinoic acid-induced neurite outgrowth in N2A cells; however, butein significantly increased neurite length and induced dose-dependent apoptotic cytotoxicity in N2A cells. This study suggests that low concentration of butein can prevent CORT-induced cytotoxicity in N2A cells, and provides preliminary results supporting some of the beneficial roles of butein in neuroprotection.

Highlights

Prolonged glucocorticoid (GC) elevation due to chronic stress has been shown to reduce hippocampal volume and impair hippocampusdependent functions, leading to the development of depression (Nestler et al, 2002; Manji et al, 2001; Gould et al, 1998; Lupien et al, 1998)
When cells were incubated with 50 μM and higher concentrations of CORT, cell viabilities decreased significantly compared with the control group in a concentration-dependent manner (Fig. 1B)
N2A cells were incubated with 0.5 μM butein for 30 min and a final concentration of 50 μM CORT was added into medium

Summary

Introduction

Prolonged glucocorticoid (GC) elevation due to chronic stress has been shown to reduce hippocampal volume and impair hippocampusdependent functions, leading to the development of depression (Nestler et al, 2002; Manji et al, 2001; Gould et al, 1998; Lupien et al, 1998). Plasma GC levels are constantly controlled through a negative feedback mechanism in HPA axis regulation. The pathophysiology of depression is hypothesized to result in GC overexposure of the brain and hippocampus by HPA axis dysregulation. Because the hippocampus is sensitive to GCs, excessive GC levels causes hippocampal damage and cell loss. Neuronal cells in the brain are vulnerable to oxidative stress. Past reports have suggested that GC elevation generates reactive oxygen species (ROS) and causes damage to neuronal cells (e.g. in the hippocampus), inducing cell death via apoptosis (Sousa et al, 1999; Sato et al, 2010; Latt et al, 2018)

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Results

Conclusion