::::::::: Overview  ::::
The mission of the Brain Research Laboratory of the Department of Emergency Medicine is to combine basic, translational, and clinical research to find a safe and effective acute-stage treatment for traumatic brain injury (TBI) and stroke. Although the development of ‘clot-busting’ drugs has somewhat advanced the treatment of stroke, nothing is currently available for the treatment of TBI in the first hours when the cascade of toxic molecular events is most destructive. Clinical trials of over 50 compounds over the last 30 years have not yet led to a treatment to reduce or prevent the loss of injured brain cells and enhance functional recovery.

We are trying to change this situation. For the last 17 years, our laboratory has focused on the role of neurosteroids – primarily progesterone and its metabolites – in the treatment of TBI. Our research first looked for sex differences in TBI outcomes caused by normally circulating hormone levels, but we soon turned to examining how administered progesterone led to beneficial outcomes in brain-damaged subjects of both sexes. Our laboratory and many others around the world have shown that progesterone and allopregnanolone administered within the first 24 hours after severe TBI can lead to substantial neuronal rescue and the persistent sparing of cognitive, sensory, and motor functions.

The success of this work in animals led to an NINDS-sponsored clinical trial of progesterone in TBI patients. Progesterone reduced mortality by over 60 percent and improved functional outcomes at 30 days post-injury.

Despite these promising results, much remains to be done. To enhance the effectiveness of neurosteroid treatments, our laboratory now studies the mechanisms by which the hormones directly and indirectly affect the damaged central nervous system. We have also recently turned some of our attention to exploring the effects of neurosteroids in stroke, epidemiologically an even more serious problem than TBI.

::::::::: Active Projects  ::::
1. We are currently examining whether progesterone can have neuroprotective effects in aged male and female rats, where the hormonal milieu is very different from that of their younger counterparts. To date, nothing is known about the role of neurosteroids when stroke or TBI occurs in senescent animals. Would treatment in elderly patients be beneficial or harmful? For example, although women may recover better than men, especially after a stroke, this difference disappears in post-menopausal women. We would like to know whether progesterone can enhance recovery in aged males and females.

2. Although young adults and the aged make up the majority of stroke and TBI victims, there are substantial numbers of pediatric cases as well. We know virtually nothing about the role of neurosteroids in repair of the damaged immature brain and we are now developing a pediatric model of hypoxic injury to test neurosteroid effects. In sum, we want to examine progesterone-induced recovery across the developmental spectrum.

3. We are also studying the differences between progesterone and allopregnanolone in stroke and TBI. Our preliminary work suggests that progesterone may be more effective in the treatment of TBI while allopregnanolone seems to work better in stroke – although both neurosteroids confer neuroprotection and reduce the inflammatory processes that usually accompany and increase the extent of brain damage.

4. As we advance forward more clinical testing, it becomes important to know how neurosteroids act to enhance functional recovery. Working through the classical intra-nuclear receptors is only one possible mechanism for enhancing repair in the damaged brain. We are trying to determine what those non-receptor-mediated responses are so that we can design more effective neurosteroid treatments for both stroke and trauma.

::::::::: Resources  ::::
We enjoy recently modernized laboratory and animal housing space in the Winship Cancer Center. We also have state-of-the-art facilities for surgical manipulations, behavioral testing, and for most of the immunocytochemical and molecular biological assays necessary in our research. The Brain Research Laboratory is currently supported by NIH-NINDS funding.

::::::::: Fellowships  ::::
No intramural fellowships are currently available. Post-doctoral investigators typically receive support through PI-initiated research grants or other extramural programs. Graduate students accepted into the program can expect approximately three years of support from the Graduate School and are then expected to transfer to individual NIH fellowships or R-01 grants.

::::::::: Contact Us  ::::
If you would like additional information about the Brain Research Laboratory, please contact Donald G. Stein, Ph.D or Leslie McCann, M.A.