Neurocritical Care Progesterone for Neuroprotection in Pediatric Traumatic Brain Injury Courtney L. Robertson, MD, FCCM1,2; Emin Fidan, MD3; Rachel M. Stanley, MD, MHSA4; Corina Noje, MD1,2; Hülya Bayir, MD3,5 Objective: To provide an overview of the preclinical literature on neuroinflammation, oxidative stress, and excitotoxicity. More than progesterone for neuroprotection after traumatic brain injury and 40 studies have used progesterone for treatment after traumatic to describe unique features of developmental brain injury that brain injury in adult animal models, with results summarized in should be considered when evaluating the therapeutic potential tabular form. However, very few studies have evaluated proges- for progesterone treatment after pediatric traumatic brain injury. terone in pediatric animal models of brain injury. To date, two Data Sources: National Library of Medicine PubMed literature human phase II trials of progesterone for adult traumatic brain review. injury have been published, and two multicenter phase III trials Study Selection: The mechanisms of neuroprotection by proges- are underway. terone are reviewed, and the preclinical literature using proges- Conclusions: The unique features of the developing brain from that terone treatment in adult animal models of traumatic brain injury of a mature adult brain make it necessary to independently study is summarized. Unique features of the developing brain that progesterone in clinically relevant, immature animal models of trau- could either enhance or limit the efficacy of neuroprotection by matic brain injury. Additional preclinical studies could lead to the progesterone are discussed, and the limited preclinical literature development of a novel neuroprotective therapy that could reduce using progesterone after acute injury to the developing brain is the long-term disability in head-injured children and could poten- described. Finally, the current status of clinical trials of progester- tially provide benefit in other forms of pediatric brain injury (global one for adult traumatic brain injury is reviewed. ischemia, stroke, and statue epilepticus). (Pediatr Crit Care Med Data Extraction and Data Synthesis: Progesterone is a pleiotro- 2015; 16:236–244) pic agent with beneficial effects on secondary injury cascades Key Words: children; developmental brain injury; infant; that occur after traumatic brain injury, including cerebral edema, neurosteroid; trauma 1Department of Anesthesiology and Critical Care Medicine, Johns Hop- kins University School of Medicine, Baltimore, MD. 2Department of Pediatrics, Johns Hopkins University School of Medicine, very year in the United States alone, nearly a half million Baltimore, MD. children sustain traumatic brain injury (TBI), and ~3,000 3 Department of Critical Care Medicine, Safar Center for Resuscitation children per year die of these injuries (Centers for Disease Research, University of Pittsburgh, Pittsburgh, PA. E 4Departments of Emergency Medicine and Pediatrics, University of Michi- Control and Prevention). Despite recent advances in neuroin- gan, Ann Arbor, MI. tensive care and reduction in the overall mortality rate (1), the 5Department of Environmental and Occupational Health, Center for Free long-term morbidity of severe TBI in childhood remains high. Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA. Survivors of pediatric TBI suffer from many long-term physical, Supplemental digital content is available for this article. Direct URL citations cognitive, psychological, and emotional impairments (2, 3). After appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/pccmjournal). TBI, a cascade of secondary insults leads to cell death. The devel- Dr. Stanley received support from the Health Resources and Services Admin- oping brain may be uniquely vulnerable to some of these second- istration (1H34MC193530100). Her institution received grant support from ary insults, due to maturational features. The steroid hormone the Health Resources and Services Administration (planning grant to plan a progesterone has been studied extensively in preclinical models of trial of progesterone for pediatric traumatic brain injury). Dr. Noje is employed by Johns Hopkins School of Medicine. Dr. Bayir received support for article adult TBI. It provides multiple mechanisms of neuroprotection research from the National Institutes of Health (NS061817 and NS076511). that could be very important after pediatric TBI, such as reducing Her institution received grant support from NINDS. The remaining authors cerebral edema, as well as anti-inflammatory, antioxidant, anti- have disclosed that they do not have any potential conflicts of interest. apoptotic, and antiexcitatory properties. This review will high- For information regarding this article, E-mail: [email protected]; bayihx@ upmc.edu light progress to date in using progesterone for neuroprotection Copyright © 2015 by the Society of Critical Care Medicine and the World after TBI and will discuss unique features of developmental brain Federation of Pediatric Intensive and Critical Care Societies injury that should be considered when evaluating the therapeutic DOI: 10.1097/PCC.0000000000000323 potential for progesterone treatment after pediatric TBI. 236 www.pccmjournal.org March 2015 • Volume 16 • Number 3 Neurocritical Care PROGESTERONE IN PRECLINICAL STUDIES OF ADULT TBI Over the last 25 years, many preclinical studies have demon- strated neuroprotection by progesterone after TBI in adult ani- mal models (4–13). Stein (14) began investigating progesterone after observing that female rats recovered better than male rats after TBI. In initial studies, they compared three groups of adult rats (normal male rats, normally cycling female rats in proes- trus, and pseudopregnant female rats with high circulating pro- gesterone) (15). They found that normal female rats had less brain edema at 24 hours after TBI compared with male rats and that the pseudopregnant females had remarkably little brain edema compared with the other two groups. Follow-up studies showed that exogenous treatment of male rats with progester- Figure 1. The putative neuroprotective mechanisms of the pleiotropic agent progesterone are detailed in the figure. These mechanisms all play one reduced cerebral edema, lesion volume, and neuronal loss a role in secondary injury following traumatic brain injury. BBB = blood- after TBI (15). Similarly, Bramlett and Dietrich (16) compared brain barrier, GABA = γ-aminobutyric acid. male rats, normal female rats, and ovariectomized female rats showing the smallest lesion volumes in normal females com- accompanied by increased expression of AQP4 in the peri- pared with the other two groups. Stein’s group (17) also showed contusional area and lateral ventricles. In contrast, there was that the therapeutic window for progesterone could be up to 24 a significant decrease in AQP4 expression in the tissue sur- hours after TBI, when targeting cerebral edema, and that there rounding the third ventricle. Progesterone treatment decreased is a u-shaped dose-response curve for improving cognitive brain water content and AQP4 expression in the pericontu- outcomes, including memory acquisition in the Morris water sional areas and in the tissue surrounding the lateral ventricles, maze (18). In addition, they described potentially detrimental while increasing AQP4 expression in the tissue adjacent to symptoms of abrupt progesterone withdrawal that may war- the third ventricle. The authors speculated that by increasing rant tapering (19). Other investigators have confirmed the neu- AQP4 expression in the osmosensory areas in the hypothala- roprotective properties of progesterone using a variety of TBI mus surrounding the third ventricle, progesterone might have models in adult animals. We performed a PubMed search of all contributed to enhanced water drainage leading to preserva- original preclinical research studies of progesterone use in adult tion of osmotic equilibrium in the brain. Corroborating the TBI published between 1992 and 2013. The 46 identified stud- importance of AQP4 as a therapeutic target for pediatric TBI, ies (96–125) are summarized in Supplemental Table 1 (Supple- a recent study showed decreased edema formation, decreased mental Digital Content 1, http://links.lww.com/PCC/A129). In BBB disruption, and improved motor and long-term cognitive addition, a recent preclinical systematic review summarized the function with inhibition of AQP4 expression by injection of key aspects of progesterone treatment for neuroprotection after small-interfering RNA targeting AQP4 after controlled cortical TBI and cerebral ischemia in adult animals, looking at effects impact injury in the developing brain (28). on lesion volume (20). The main finding was that progester- Progesterone has been shown to have anti-inflammatory one was neuroprotective, but limitations in the literature were effects by suppressing generation of proinflammatory cyto- identified, including insufficient examination of dose-response kines and reducing microglial activation (4, 23, 24, 29, 30). relationships, therapeutic windows, and evaluation in female or These anti-inflammatory effects could be especially important aged adult animals. after TBI, where marked neuroinflammation contributes to many aspects of secondary brain injury, such as vascular endo- MECHANISM OF NEUROPROTECTION BY thelial injury and disruption