Progesterone treatment alters neurotrophin/proneurotrophin balance and receptor expression in rats with traumatic brain injury

Purpose: The neuroactive steroid progesterone (PROG) has been shown to be an effective treatment for traumatic brain injury (TBI) both in animal models and in humans, but the signaling pathways involved have not yet been fully described. Here we characterize the protein expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and their pro-proteins and receptors following PROG treatment for TBI. Methods: To evaluate whether PROG treatment given after TBI alters mature and proneurotrophin protein balance and the expression of receptors involved in apoptotic and cell survival signaling, we used Western blots in tissue obtained 24 h, 72 h, and 7 days after injury from rats with bilateral frontal cortical contusions. Results: Compared to controls, PROG reduced levels of pro-apoptotic NGF precursor (proNGF) at 24 h and 7 days post-injury, reduced levels of pro-apoptotic BDNF precursor (proBDNF) and the BDNF receptor TrkB at all time points, and increased levels of mature NGF at 72 h. Levels of mature BDNF were decreased at 24 and 72 h. These observations were associated with reduced markers of apoptosis and improved behavioral parameters in PROG-treated rats. Conclusions: Some of PROG's protective effects after TBI are mediated, in part, by simultaneous induction of pro-survival neurotrophin signaling and inhibition of apoptotic proneurotrophin signaling.