However, unlike other steroid hormones, PROG is synthesized directly in the brain by oligodendrocytes and neurons,47,72 so it can be considered a “neurosteroid” beyond its role as a sex hormone. In pregnant, females, PROG levels increase 10- to 15-fold and remain high throughout, gestation, but in humans, within 1 to 2 hours after parturition, levels drop precipitously. Why? It is becoming more evident that PROG’s multiple mechanisms of action have evolved primarily to protect, the developing fetus from oxidative stress and immune-inflammatory rejection reactions. The

hormone is now thought to play a critical role in neuronal-glial signaling and normal neuronal development. Many of the Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical processes of tissue repair, including cells in the CNS, recapitulate steps that take place during development.73,74 Based on what we have seen following treatment with PROG in adult subjects with brain injury, we hypothesize that its role

in protecting the fetus during development recapitulates its effects in the treatment of traumatic and degenerative disorders of the brain and CNS. It is also important to note that, PROG and its metabolites such as ALLO are pleiotropic―they act at multiple receptor sites, not just, at the classical intranuclear PR. These mechanisms are discussed in a number of recent reviews that highlight the rapid, nongenomic actions Inhibitors,research,lifescience,medical of PROG in the CNS and other tissue affected by injur}’ or degenerative diseases.75,76 Conclusion Many other drugs have failed in clinical trial because they seem to act only at one or a few receptor sites, or only affect, the expression of genes implicated in the injury cascade. To reiterate, Inhibitors,research,lifescience,medical it is suggested here that TBI and stroke are systemic diseases that GSK126 cost produce wide-spread negative symptoms in many tissue and organ systems throughout the body. An agent or drug that acts systemically to reduce the inflammatory cascade, while at the same time

providing trophic support, to damaged nerve cells, is more likely to have a beneficial outcome than an agent, that acts only at a single target Inhibitors,research,lifescience,medical in the brain. This is where PROG seems to shine as a therapeutic agent. Over 25 years of preclinical research by our laboratory and now many others have identified and defined many of the physiological mechanisms underlying PROG’s benefits. Given its relatively high safety profile, ease of administration, low cost, and ready availability, PROG and its metabolites should be considered as a potential treatment, option―especially because in brain injury little all else is currently available. Acknowledgments Donald Stein is entitled to royalty from products of BHR Pharma and may receive research funding from BHR, which makes products related to this research. In addition, the author serves as consultant to BHR and receives compensation for these services. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies.