A clinical/translational perspective: can a developmental hormone play a role in the treatment of traumatic brain injury?

Despite decades of laboratory research and clinical trials, a safe and effective treatment for traumatic brain injury (TBI) has yet to be put into successful clinical use. I suggest that much of the problem can be attributed to a reductionist perspective and attendant research strategy directed to finding or designing drugs that target a single receptor mechanism, gene, or brain locus. This approach fails to address the complexity of TBI, which leads to a cascade of systemic toxic events in the brain and throughout the body that may persist over long periods of time. Attention is now turning to pleiotropic drugs: drugs that act on multiple genomic, proteomic and metabolic pathways to enhance morphological and functional outcomes after brain injury. Of the various agents now in clinical trials, the neurosteroid progesterone (PROG) is gaining attention despite the widespread assumption that it is "just a female hormone" with limited, if any, neuroprotective properties. This perspective should change. PROG is also a powerful developmental hormone that plays a critical role in protecting the fetus during gestation. I argue here that development, neuroprotection and cellular repair have a number of properties in common. I discuss evidence that PROG is pleiotropically neuroprotective and may be a useful therapeutic and neuroprotective agent for central nervous system injury and some neurodegenerative diseases.