The Dual Dose-Dependent Effects of Corticosterone on Hippocampal Cell Apoptosis After Traumatic Brain Injury Depend on the Activation Ratio of Mineralocorticoid Receptors to Glucocorticoid Receptors.

Bin Zhang,Baiyun Liu,Jinqian Dong,Qianqian Ge,Fei Niu,Xiaojian Xu,Qiongyu Yan,Shenghua Lu,Mengshi Yang,Yuan Zhuang

doi:10.3389/fphar.2021.713715

Abstract

In our recent studies, we reported that mineralocorticoid receptor (MR) had the opposite effects of glucocorticoid receptor (GR) on neural cell survival after traumatic brain injury (TBI). However, whether short-term use of high-dose natural glucocorticoids, which are mixed agonists of both MR and GR, leads to neurotoxic effects by inducing excessive GR activation is unclear, as is the threshold GR activation level and the possible signaling pathways remain unclear. In this study, we examined the dual dose-dependent effects of corticosterone (CORT) on spatial memory, hippocampal cell survival and receptor-mediated downstream signaling pathways after TBI. We found that different doses of CORT exhibited dual effects on hippocampal cell survival and rat spatial memory. Low doses of CORT (0.3 and 3 mg/kg) significantly increased MR activation, upregulated Akt/CREB/Bad phosphorylation and Bcl-2 concentration, reduced the number of apoptotic neural cells, and subsequently improved rat spatial memory. In contrast, a high dose of CORT (30 mg/kg) exerted the opposite effects by overactivating GR, upregulating P53/Bax levels, and inhibiting Erk/CREB activity. The results suggest that the neuroprotective and neurotoxic effects of endogenous GC depend on a threshold level and that a higher dose of GC, even for short-term use, should be avoided after TBI.

Highlights

Since their discovery in the 1950s, glucocorticoids (GCs), especially synthetic GCs, have been widely used to treat a wide range of diseases
Our recent study showed that mild motor function disturbance occurred immediately after Cortical Impact (CCI), but was improved rapidly within 24 h, and the motor test showed no difference among rats in all experimental groups (Zhang et al, 2020b)
We previously found that continuous and full activation of mineralocorticoid receptor (MR) induced by low-dose CORT protected hippocampal neural cells from apoptosis in the acute phase after traumatic brain injury (TBI), while overactivation of glucocorticoid receptor (GR) by DEX promoted apoptosis (Zhang et al, 2020a; Zhang et al, 2020b)

Summary

Introduction

Since their discovery in the 1950s, glucocorticoids (GCs), especially synthetic GCs, have been widely used to treat a wide range of diseases. Their clinical use is limited by severe adverse effects, such as diabetes mellitus, osteoporosis, hypertension, and increased risk of infection (Rhen et al, 2005; Cain et al, 2017; Vandewalle et al, 2018). Experimental studies have revealed that sufficient activation of MR is crucial for the normal functions of many structures in the brain, including the hippocampus and hypothalamus and that excessive or prolonged activation of GR caused by long-term synthetic GR agonist treatment or excessive endogenous GCs secretion (for example, due to chronic stress or Cushing syndrome) causes severe cognitive, stress, and mood disorders (Krugers et al, 2010; Fardet et al, 2012; de Kloet et al, 2014, 2018; Burkhardt et al, 2015)

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