Abstract
Background: Our recent studies reported the opposite effects of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) on neuron survival after traumatic brain injury (TBI). However, as a mixed agonist for MR and GR, whether short term use of high-dose endogenous glucocorticoids exerts neurotoxic effects by excessive activation of GR, what is the set-point, and the possible signaling pathways remain unclear. This study examined the dose-dependent dual effects of corticosterone (CORT) on the spatial memory, the survival of hippocampal neurons and the possible receptor-mediated downstream signaling pathways after TBI.Methods: Based on controlled cortical impact (CCI) and CORT treatments, Sprague-Dawley rats (n=168) were randomly divided into the sham, CCI, CCI + CORT1 (0.3 mg/kg), CCI + CORT2 (3 mg/kg), CCI + CORT3 (30 mg/kg), CCI + CORT1 + spirolactone (spirolactone: 50 mg/kg/d), and CCI + CORT3 + RU486 (RU486: 50 mg/kg/d) groups. Brain tissues were collected on postinjury day 3 and processed for histology and western blot analysis.Results: On postinjury day 3, we tested the learning and memory ability, neuronal apoptosis in the hippocampus, activation levels of MR and GR, Bcl-2 family proteins, and apoptosis-related intracellular signaling pathways. We found that different doses of CORT exhibited dual effects on the survival of hippocampal neurons and the spatial memory. Lower doses of CORT (0.3, 3 mg/kg) significantly increased the activation of MR, upregulated the phosphorylation of Akt/CREB/Bad and the Bcl-2 expression, reduced the number of apoptotic neurons, and subsequently improved the spatial memory. In contrast, higher dose of CORT (30 mg/kg) exerted opposite effect by over activating GR, upregulating the expressions of P53/Bax, and inhibiting the Erk/CREB activities. Conclusion: The results suggest that there is a threshold between the neuroprotective and neurotoxic effects of endogenous GC, higher dose of which, even for short-term use, should also be avoided after TBI.
Neurotrophin-mediated neuroprotection of hippocampal neurons following traumatic brain injury is not associated with acute recovery of hippocampal function
