Objective: TBI is a major cause of acquired disability in children.. The commonest sequel is cognitive dysfunction, resulting from selective hippocampal damage. Glucocorticoids and mineralocorticoids are steroid hormones which act through specific receptors (GR and MR), playing a critical role in hippocampal neuronal survival and plasiticity. Neurotrophins may mediate the actions of glucocorticoids on neuronal survival. The study aim was to investigate the impact of therapeutic modulation of GR/MR balance on the neurotrophic response to TBI, using an experimental model..

Methods: Adult male Wistar rats were subjected to moderate fluid percussion injury (FPI) or sham-injury under full general anaesthesia. One hour pre-surgery, subjects were administered control vehicle; GR-blocker (mifepristone) or MR-blocker (spironolactone). Animals were sacrificed six hours post-surgery. In situ hybridisation studies were performed, using radiolabelled oligoprobes to mRNA for Brain Derived Neurotrophic Factor (BDNF) and its tyrosine receptor (Trk-B). ANOVA compared optical density measurements for BDNF and Trk-B mRNA between six groups: 1) sham-injury/vehicle; 2) FPI/vehicle; 3) sham-injury/ spironolactone; 4) FPI/spironolactone; 5) sham-injury/mifepristone; 6) FPI/mifepristone.

Results: Significant group differences were seen for BDNF and Trk B mRNA expression in all hippocampal regions (DG, CA1, CA2, CA3), both ipsilateral and contralateral to injury (all, p<0.0001). Post-hoc analysis demonstrated significant differences between sham- injured and FPI rats and between FPI spironolactone rats and FPI mifepristone or vehicle rats for BDNF mRNA (e.g. ipsliateral CA1, FPI/mifepristone vs. FPI/spironolactone p=0.002; CA2, FPI/vehicle vs. FPI/spironolactone p<0.0001; CA3, FPI/vehicle vs. FPI/spirolactone p<0.0001, FPI/mifepristone vs. FPI spironolactone p=0.001) and Trk-B mRNA (e.g. DG, FPI/mifepristone vs. FPI spironolactone p=0.001; CA2, FPI/vehicle vs. FPI/spironolactone p<0.0001; CA3, FPI/vehicle vs. FPI/spironolactone p<0.0001, FPI/mifepristone vs. FPI/ spironolactone p=0.017). Pre-injury spironolactone enhanced TBI-induced up-regulation of BDNF and Trk-B mRNA.

Conclusions: Selective blockade of MRs by spironolactone enhances the neurotrophic response to experimental TBI. Further research will explore the impact on histological and cognitive outcome.