Mild traumatic brain injury (TBI) is common among veterans who have served in OEF/OIF
(Operation Enduring Freedom in Afghanistan/Operation Iraqi Freedom) and other theatres.
Delayed symptoms may occur following TBI, including cognitive symptoms (impaired attention,
processing speed, executive functioning), as well as behavioral symptoms such as anxiety,
depression, and irritability (Fann et al. 2004; Holsinger et al. 2002). Neuroactive steroids
have neuroprotective effects in rodent models of TBI (Djebaili et al. 2005; Djebaili et al.
2004; He et al. 2004; Pettus et al. 2005; Roof et al. 1997) and the neuroactive steroid
pregnenolone and its sulfated derivative also markedly enhance learning and memory in rats
(Akwa et al. 2001; Flood et al. 1992; Flood et al. 1995; Vallee et al. 1997; Vallee et al.
2003). In humans, reductions in pregnenolone (George et al. 1994) and its GABAergic
metabolite allopregnanolone (Uzunova et al. 1998) have been associated with depressive
symptoms. Pharmacological intervention with the neuroactive steroid pregnenolone could
therefore result in a multi-targeted treatment approach, potentially improving cognitive
deficits as well as anxiety and depression symptoms following TBI.