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.

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.

Corticosterone Replacement Alleviates Hippocampal Neuronal Apoptosis and Spatial Memory Impairment Induced by Dexamethasone via Promoting Brain Corticosteroid Receptor Rebalance after Traumatic Brain Injury.

The balance of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) is indispensable for maintaining the normal function and structure of the hippocampus. However, changes in GR/MR and their effect on the survival of hippocampal neurons after traumatic brain injury (TBI) are still unclear. Previous studies have indicated that high-dose glucocorticoids (GC) aggravate hippocampal neuronal damage after TBI. We hypothesize that the imbalance of GR/MR expression and activation caused by injury and irrational use of dexamethasone (DEX) aggravates post-traumatic hippocampal apoptosis and spatial memory dysfunction, but that restoration by refilling MR and inhibiting GR promotes the survival of neurons. Using rat controlled cortical impact model, we examined the plasma corticosterone (CORT), corticosteroid receptor expression, apoptosis, and cell loss in the hippocampus, and, accordingly, the spatial memory after TBI and GC treatment within 7 days. Plasma CORT, MR, and GR expression level were significantly reduced at 2 days after TBI. Accordingly, the number of apoptotic cells also peaked at 2 days. Compared with the TBI control group, DEX treatment (5 mg/kg) significantly reduced plasma CORT, upregulated GR expression, and increased the number of apoptotic cells and cell loss, whereas CORT replacement (0.3 mg/kg) upregulated MR expression, inhibited apoptosis, and improved spatial memory. The deleterious and protective effects of DEX and CORT were counteracted by spironolactone and mifepristone respectively. The results suggest that inhibition of GR by RU486 or the refilling of MR by CORT protects hippocampal neurons and alleviates spatial memory impairment via promoting GR/MR rebalancing after TBI.