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Progesterone in the treatment of acute traumatic brain injury: a clinical perspective and update
Neuroscience 191 (2011) 101–106
REVIEW PROGESTERONE IN THE TREATMENT OF ACUTE TRAUMATIC BRAIN INJURY: A CLINICAL PERSPECTIVE AND UPDATE D. G. STEIN*
BACKGROUND: TRAUMATIC BRAIN INJURY IS A SERIOUS PUBLIC HEALTH CONCERN
Brain Research Laboratory, Department of Emergency Medicine, Emory University, 1365 B Clifton Road NE, Suite 5100, Atlanta, GA 30322, USA
In the United States, civilian traumatic brain injury (TBI) is by far the most common cause of death in men under the age of 35. It is also a major problem in the elderly, among whom falls contribute to head injury, which then leads to increased morbidity and risk of death. Many people do not know that TBI is also a major factor in morbidity and disability and a leading cause of death in children, resulting in 7400 deaths, more than 60,000 hospitalizations, and over 600,000 Emergency Department visits annually in the US alone (Centers for Disease Control and Prevention, 2010). Pediatric TBI can cause developmental impairments and life-long disability. Over 300,000 pediatric head injuries result from contact sports and can have long-term consequences even though the initial injuries are often said to be “minor” or “mild” (Schneier et al., 2006). TBI has been getting increased public attention in the US, at least in part because of the large number of concussive blast injuries suffered in the Iraq and Afghanistan conflicts. US government sources indicate that, from 2003 to 2007, as many as 43,779 surviving combat casualties were diagnosed with varying degrees of brain injury caused by explosive devices (Ippolito, 2007), and there have been suggestions in the national press that even these numbers are under-reported. As of this writing, no new pharmacotherapy for TBI has entered general clinical practice since the National Institutes of Health (NIH) began profiling articles in this field. Glucocorticoids such as dexamethasone, once the gold standard for TBI treatment, are now considered detrimental to central nervous system (CNS) repair (Alderson and Roberts, 2000; Vink and Van Den Heuvel, 2004; Watson et al., 2004; Gomes et al., 2005). The Corticosteroids after Significant Head Injury (CRASH) trial, with more than 10,000 subjects in 40 countries, was stopped when it was found that the treatment group had a significantly higher mortality rate than the control group (Roberts et al., 2004; Edwards et al., 2005). More recently, an NIH-funded clinical trial of magnesium sulfate was terminated for the same reason (see Temkin et al., 2007 for details). Cyclosporine, an immunosuppressive drug in clinical use, has exhibited neuroprotective properties in animal models of TBI (Vink and Nimmo, 2009; Xiong et al., 2009), where it appears to work by preserving mitochondrial metabolism and function. Cyclosporine has been tested in a single-center, 40-patient, randomized, double-blind trial for
Abstract—Despite decades of laboratory research and clinical trials, a safe and effective treatment for traumatic brain injury has yet to reach clinical practice. The failure is due in part to the prevalence of a reductionist philosophy and research praxis that targets a single receptor mechanism, gene, or brain locus. This approach fails to account for the fact that traumatic brain injury is a very complex disease caused by a cascade of systemic toxic events in the brain and throughout the body. Attention is now turning to pleiotropic drugs that act on multiple genomic, proteomic, and metabolic pathways to enhance morphological and functional outcomes after brain injury. Of the agents now in clinical trial, the neurosteroid progesterone appears to hold considerable promise. Many still assume that progesterone is “just a female hormone” with limited, if any, neuroprotective properties, but this view is outdated. This review will survey the evidence that progesterone has salient pleiotropic properties as a neuroprotective agent in a variety of central nervous system injury models. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. © 2011 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: progesterone, neuroprotection, traumatic brain injury, neurosteroid, clinical trials, pharmacotherapy. Contents Background: traumatic brain injury is a serious public health concern 101 Why has it been so hard to find a treatment for brain injury? 102 Is progesterone a good candidate for TBI pharmacotherapy?102 Why is progesterone more likely to succeed as a treatment? 102 Progesterone phase II clinical trials 103 Despite the promising results thus far, questions remain 103 Progesterone is now in Phase III clinical trials 104 There are still questions about PROG’S effectiveness 104 Conclusions 105 Disclosures 105 References 105 *Tel: ⫹1-404-712-9704; fax: ⫹1-404-727-2388. E-mail address: [email protected] (D. G. Stein). Abbreviations: CNS, central nervous system; DRS, Disability Rating Scale; GOS, Glasgow Outcome Scale; GSC, Glasgow Coma Scale; HRT, hormone replacement therapies; MPA, medroxyprogesterone acetate; NIH, National Institutes of Health; PROG, progesterone; TBI, traumatic brain injury.
0306-4522/11 $ - see front matter © 2011 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2011.04.013
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dosing and safety (Hatton et al., 2008) in patients with severe TBI. Although it has only a 4-h window for treatment, and mortality rates were not reduced, the drug appeared to be well-tolerated and did lead to somewhat better functional outcomes in patients surviving up to and past 6 months post-injury. At present, it is not certain that a Phase III trial will proceed. Other drugs now in Phase I or Phase II studies for safety and preliminary evidence of efficacy include erythropoietin, a hormone which stimulates the formation of red blood cells and has been shown to have neuroprotective properties in animal TBI models; darbepoetin (Aranesp™) (Grasso et al., 2009; Mammis et al., 2009), a modified form of erythropoietin used in the treatment of anemia in dialysis patients which reduces oxidative stress in injured brain tissue; Premarin™, a commercial form of conjugated equine estrogens; methylphenidate, an amphetamine-like drug used to treat attention deficit disorder; and hypotonic saline for the treatment of intracranial hypertension. A randomized, double-blind trial (close to 200 patients) for Citicoline, an acetylcholinesterase inhibitor sold as a food supplement and thought to enhance cognitive performance in Alzheimer’s patients, is in progress. A previous Phase III trial using this agent to treat ischemic stroke did not provide any evidence of efficacy compared to controls (Clark et al., 2001). Several forms of human growth hormone such as NNZ-2566 are being tested in an industrysponsored multi-center trial. Recent trials with Genotropin™ and Somatotropin™ have been withdrawn.
WHY HAS IT BEEN SO HARD TO FIND A TREATMENT FOR BRAIN INJURY? TBI is a complex systemic disorder. When the brain is injured, the physiology of the entire organism changes. This means that very often, the consequences of a “brain injury” are not limited to the brain itself. Disregarding the complexity of TBI, biomedical researchers often focus on developing a drug with a limited, specific mechanism of action—for example, an agent that acts on a single neurotransmitter (e.g. acetylcholine, gamma-Aminobutyric acid (GABA)), or binds primarily or exclusively to a specific receptor (e.g. N-methyl-D-aspartic acid (NMDA)), in the expectation that blocking the channel will prevent excessive calcium influx leading to cell death in the brain and that all will be well thereafter. This approach fails to address acute simultaneous changes produced by the TBI in other organs such as the gut, spleen, thymus, and liver. All these changes create a further cascade of injury that can contribute to the brain injury syndrome. Many physiological processes can be affected by a brain injury. More than 10 years ago Shohami et al. (Shohami et al., 1999) reported that closed head injury can produce oxidative stress reactions in heart, kidney, lung, liver, and other body tissues in the first 24 h after injury. In another study (Glantz et al., 2005), transient ischemia produced by middle cerebral artery occlusion followed by reperfusion reduced anti-oxidant reserves in brain and peripheral organs such as the heart, liver, and
lung, suggesting that after a stroke, the whole body is subjected to oxidative stress. In several other reports, ischemic stroke has been shown to produce a dramatic reduction in the size of the spleen and thymus gland within hours after the injury (Offner et al., 2006). A number of studies (Hang et al., 2005, 2007; Chen et al., 2007; Zhou et al., 2007) report similar findings—that brain injuries can induce marked expression of inflammatory factors like tumor necrosis factor-alpha (TNF-␣) or nuclear factor-kappa B (NF-B) and interleukin-6 (IL-6) in the intestinal mucosa of the gut. The complex nature of these systemic inflammatory problems is more obvious in patients with moderate to severe TBI, but both the human and animal literatures suggest that multiple organ injury/dysfunction can manifest itself even when an injury is relatively mild (Utagawa et al., 2008; Vilalta et al., 2008). Given what we now know about the progression of a brain injury in trauma or stroke, there is an urgent need for an agent that works at multiple levels of injury, on a variety of receptors that inhibit the destructive cascade of events following TBI, and that stimulates the tropic and trophic events needed to enhance repair and regenerative processes.
IS PROGESTERONE A GOOD CANDIDATE FOR TBI PHARMACOTHERAPY? Hidden in plain sight, the hormone progesterone (PROG) may be the pleiotropic drug that can markedly attenuate the complex injury cascade associated with TBI. After more than two decades of pre-clinical research on the use of PROG in TBI, it is clear that this neurosteroid has many complex properties affecting the mechanisms involved in neuroprotection and repair after various kinds of CNS injury (Sayeed and Stein, 2009; Stein and Hurn, 2009). There are currently more than 180 articles showing the neuroprotective effects of PROG from more than two dozen laboratories, using four species including humans and 22 different models of injury. Much of this work has been recently reviewed (Toung et al., 2004; Cutler et al., 2005; Fee et al., 2007; Schumacher et al., 2007; Sayeed and Stein, 2009; Stein and Hurn, 2009; Vink and Nimmo, 2009). Why is progesterone more likely to succeed as a treatment? PROG’s effectiveness as a neuroprotective agent is probably related to its protective properties for both males and females during development, when the fetus of both sexes is exposed to high levels of maternal PROG during almost the entire period of gestation. Many of the processes involved in CNS repair after brain injury are thought to recapitulate what takes place in normal brain development (see Stein and Hoffman, 2003 for review). PROG is synthesized by oligodendrocytes and in excitatory neurons in the brains of both males and females in roughly equal amounts (Baulieu and Robel, 1990; Baulieu, 1991; Schumacher et al.,
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1996; Baulieu et al., 2001). Hirst and colleagues (Hirst et al., 2009) point out that in many species including humans, PROG and allopregnanolone play a role in reducing excessive excitotoxicity and inflammation while maintaining normal levels of cell proliferation and apoptosis in the developing brain. During development much of the circulating PROG comes from the placenta, but because they found that PROG is synthesized in the CNS, Baulieu and his colleagues were the first to recognize it as a true neurosteroid (Baulieu and Robel, 1990; Baulieu, 1991; Stein and Hoffman, 2003) that can play a key role in sustaining levels of myelin in some types of neurodegenerative disorders (Schumacher et al., 2008; De Nicola et al., 2009; Labombarda et al., 2009; Leitner, 2010). Keeping in mind that PROG is a pleiotropic developmental (“pro-gestational”) hormone will help us to understand why it has promise as a treatment for brain injury in adults (Kelleher et al., 2011). Progesterone phase II clinical trials Two independent Phase II clinical trials have now shown evidence of PROG’s promise for the treatment of acute TBI. ProTECT I (Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment) was a National Institutes of Neurological Disorders and Stroke-supported, randomized, double-blind, placebo-controlled trial of 100 patients suffering from moderate to severe brain injury (Glasgow Coma Scale (GSC) scores of 4 –12) (Wright et al., 2007). In the single center study the primary aim was to determine the safety of the PROG infusion; a secondary aim was to gather preliminary evidence of beneficial effect. Exposure to the hormone treatment was optimized with a four PROG to one placebo randomization design. Seventy-three percent of the study patients were males. Approximately 76% of the patients had blunt head trauma resulting from automobile accidents. Patients enrolled in the study were admitted only with proxy consent. On average, obtaining consent took about 6 h after admittance, meaning that the treatment was delayed for at least 6 h after the TBI. The group that was given PROG was started on an i.v. drip of 0.71 mg/kg/h for the first hour which was then reduced to 0.50 mg/kg/h for the next 71 h. A Data Safety Monitoring Board found no serious adverse events attributed to the PROG treatment. Patients in the PROG group remained in a coma longer, but demonstrated more than a 50% reduction in mortality at 30 days compared to the controls (P⬍0.06). The group diagnosed with moderate injuries showed significant “encouraging signs of improvement” on their Disability Rating Scale (DRS) outcome at 30 days compared to patients receiving placebo (P⬍0.02). The ProTECT I results were later supported by another single-center trial in China of 159 severely brain-injured subjects (GCS ⱕ8) (Xiao et al., 2008) which tracked patient outcomes for a longer period of up to 6 months following enrollment in the trial. In this 1:1 randomized, double-blind, placebo-controlled trial, the 82 subjects in the PROG group were treated beginning within 8 h of injury and continuing for 5 days with intramuscular injections of PROG (1.0 mg/kg)
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every 12 h. The PROG group had significantly better survival as well as functional outcomes at both 3 and 6 months than the 77 patients given placebo. A dichotomized analysis showed that at the 3-month follow-up, 47% of the PROGtreated patients showed better functional outcomes on the Glasgow Outcome Scale (GOS) compared to 31% of the placebo group (P⬍0.034). At the 6-month follow-up the results were similar, with favorable outcomes in 58% of the PROG group compared to 42% of the placebo group (P⬍0.048). The PROG group had 18% mortality at 6 months, while the placebo group had 32%. It is important to emphasize that in both clinical trials PROG not only appeared to reduce mortality, but also reduced morbidity and improved functional outcomes (Doppenberg et al., 2004). Recently, the Department of Defense has funded a Phase II trial at the University of California, Davis, using allopregnanolone to treat moderate to severe TBI. According to a UC-Davis press release, “Researchers hope to enroll 136 male and female patients to determine whether receiving the drug minimizes brain damage, reduces or eliminates post-traumatic epileptic seizures, and improves patients’ psychological functioning and overall quality of life” (University of California—Davis, 2010). The supply of allopregnanolone will be manufactured at the UC Davis Institute for Regenerative Cures’ Good Manufacturing Practices Facility. This will be the first clinical test of allopregnanolone for TBI and may prove to be a worthwhile comparison to PROG for safety and efficacy in a clinical TBI setting. The clinicaltrials.gov website does not yet show the trial protocols, so the dosing details are not publicly available. Despite the promising results thus far, questions remain Although the pre-clinical studies show much benefit of PROG treatment and the positive results of two human clinical trials are very promising, Phase III multicenter clinical trials are needed to definitively confirm the utility of PROG for the treatment of acute TBI. So many clinical trials for TBI and stroke have failed at the Phase II–III stage, there is still considerable pessimism that a natural hormone could be more successful than the best efforts of the pharmaceutical industry. The two Phase II trials of PROG were small, singlecenter studies with a primary focus on safety. The randomization of the ProTECT I trial was not 1:1, so there were only a small number of patients who did not get the hormone and could serve as a comparison; thus a small shift in outcomes in a few patients could have led to different, less positive results. Some would argue that a dichotomized GOS is a fairly insensitive predictor of outcome and that more detailed and long-term neuropsychological testing is needed to confirm efficacy. This is an important concern, and long-term follow-up studies over a decade or more are unlikely in the present economic climate. The report from China also had some weaknesses, but it did have 1:1 randomization and they did get significant differences with a dichotomized GOS at 3 and 6 months after injury. Some experts expressed concern with the finding of a relatively high mortality rate in the placebo group. Thus, while providing grounds for opti-
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mism, the generalizability of the two Phase II trials needs to be confirmed in much larger trials—which are now underway. Progesterone is now in Phase III clinical trials An NIH-sponsored, Phase III, 31-center clinical trial for TBI is now underway across the United States. This is a 1:1 randomized, double-blind controlled trial which will examine 1140 patients. Treatment must begin within 4 h of injury in patients at least 18 years of age with a GCS score between 12 and 4. After a 1-h loading dose of 0.714 mg/kg intravenous, PROG or placebo is given by intravenous infusion at 0.5 mg/kg for 72 h, then tapered over an additional 24 h. The 4-h window of treatment is designed to optimize PROG’s neuroprotective effects by treating TBI patients as soon as possible. Food and Drug Administration approval for exemption from informed consent (EFIC) was granted for this purpose. The primary study end point is a stratified dichotomy of the GOS at 6 months. The trial will also track mortality, extent of adverse and serious adverse events, scores, and a number of other cognitive, neurological, and functional outcomes. More details can be found at http://clinicaltrials. gov/ct2/show/record/NCT00822900. In addition to the NIH study, BHR, a branch of Besins Pharma, a privately held Belgian/French pharmaceutical company, with the collaboration of the American Brain Injury Consortium (ABIC) and the European Brain Injury Consortium (EBIC), also recently began enrolling patients in a second clinical trial known as SyNAPSe. Approximately 1200 patients with severe (GCS scores of 4 – 8) closed-head TBI in whom treatment can be initiated within 8 h of injury will be enrolled in the study through 100 –120 medical centers in the United States, Western Europe, Israel, Singapore, and China. Patients are being randomized to receive a 5-day continuous i.v. infusion of PROG or placebo in a 1:1 allocation and followed for 6 months. The GOS is the primary study end point. For more information see http://www.synapse-trial.com/.
THERE ARE STILL QUESTIONS ABOUT PROG’S EFFECTIVENESS Despite the positive findings, some still argue that the results of PROG neuroprotection studies sound too good to be true for a hormonal agent that has always been under our noses (Loane and Faden, 2010 and Gibson et al., 2008). Another source of skepticism is that recent hormone replacement therapies (HRT) in post-menopausal women have been disappointing, and HRT clinical trial results led to a general concern that PROG might have no benefits or even detrimental effects. The trials were designed to use the most commonly prescribed hormones given to women in the United States. These agents were synthetic (conjugated equine estrogens combined with the progestin medroxyprogesterone acetate (MPA) and did not mimic the physiological effects of native PROG or 1--estradiol or estrone—the hormones that women naturally make. The synthetic HRT trial agents were given over long periods of time, whereas in the TBI trials, PROG treatment was administered only for 5 days post-injury
and were thus not directly comparable. From a clinical perspective, one serious area of concern is the fact that progestins are not identical to PROG in terms of how they interact with intranuclear and membrane receptor mechanisms (Ciriza et al., 2006; Jodhka et al., 2009). Thus, they should not be confused or used interchangeably in the treatment of TBI or other CNS disorders in the absence of careful evaluation for safety and efficacy. This is not a minor issue and has had serious impact for women on hormone therapy (Bethea, 2011). For example, some progestins can increase the proliferation of embryonic progenitor cells, while others such as MPA (used in the HRT trials) inhibited proliferation (Liu et al., 2010). Nilsen et al. (Nilsen et al., 2006) found that MPA exacerbated glutamate excitotoxicity in hippocampal neurons whereas native PROG protected against glutamate damage. These findings were replicated by Kaur et al. (Kaur et al., 2007), who showed that PROG protected cerebral cortical explant tissue from glutamate poisoning while MPA did not. This group showed that PROG potentially conferred neuroprotection by significantly upregulating the expression of brain-derived neurotrophic factor (BDNF), but MPA had no such effects. In fact, MPA was also recently shown to block brain mitochondrial respiration and function (Irwin et al., 2011). What we have learned from these studies is that long-term use of synthetic hormones that may mimic some, but not all of the effects of natural PROG and estrogen can have bad outcomes. While there has been considerable confirmation of the neuroprotective effects of PROG treatment after CNS injury, three recent studies have shown no positive effects after treatment with PROG. Fee et al. (Fee et al., 2007) reported no benefits of PROG after spinal cord contusion injury and 5 or 14 days of treatment, but they did see some evidence of gray-matter neuronal sparing in the 14-day treatment groups. In a stroke study, Toung et al. (Toung et al., 2004) gave senescent female rats high doses of PROG for almost 3 weeks before ischemic stroke and then abruptly terminated treatment in the post-ischemic period. No beneficial effects following this kind of treatment regime were observed, but this could be due to the age of the subjects and the triggering of PROG withdrawal syndrome in the older animals. The failure to observe a positive outcome may have been prevented by gradual tapering off of the dose (see Cutler et al., 2005 for a discussion of this issue). Gilmer et al. (Gilmer et al., 2008) created a “moderate” unilateral contusion of parietal cortex in rats and found no beneficial effects after 3 days of PROG treatment. These authors suggest that PROG might work in some injury models but not all, clearly a real possibility that can only be confirmed by further pre-clinical research. However, the broader literature does not appear to support the contention that PROG treatment for brain injury is a failed approach. In addition, two recent reviews (Gibson et al., 2008; Loane and Faden, 2010) speculate that most, if not all, preclinical studies testing neuroprotective agents, including PROG, fail to meet their criteria for pre-clinical drug development. However, despite legitimate concerns, given the large number of studies using PROG, most, if not all, of the criteria
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stipulated in the reviews by Loane and Faden, and Gibson et al. have been addressed for this agent. Studies for most of the other neuroprotective agents cited in the Loane and Faden paper may meet fewer of their criteria. However, even if all the criteria were indeed met for the animal studies, there is still no guarantee that a completely successful agent for brain repair would be discovered until large clinical trials can be conducted and evaluated.
CONCLUSIONS In over 180 pre-clinical studies, PROG or its metabolites have demonstrated neuroprotective properties in a variety of brain injury models. It is now well-documented that neurosteroids have neurotrophic, anti-inflammatory and anti-apoptotic properties, all of which contribute to reducing extent of injury and preserving neural and vascular integrity early in the injury cascade that inevitably accompanies TBI. In two preliminary clinical studies, PROG was effective in reducing mortality and improving functional outcomes when measured 30 days 3 months, and 6 months after injury. The PROG treatments were not associated with any serious adverse events. The pathologic events associated with loss of brain tissue over time are complex and heterogeneous. TBI is not a localized event implicating only neural tissue. These systemic and organismic changes result in a state of polytrauma and frailty if not corrected in the early stages of the injury. Given the complexity of the disease, a reductionistic approach to drug development that seeks a single receptor or signaling pathway or set of genes to account for the patient’s illness and recovery will explain neither the disease nor the recovery process. Given all the clinical trial disappointments to date, some healthy skepticism about PROG’s benefits is warranted, but there is still a critical need to find a safe, easy-to-administer agent with pleiotropic properties that can work at multiple levels to address the complex and systemic disruptions produced by TBI, and perhaps stroke and some neurodegenerative disorders. PROG, with its multiple anti-inflammatory, anti-apoptotic, and trophic growth-promoting properties, is essentially a developmental hormone, evolved to protect both the male and female fetus during gestation. Although PROG and its metabolites may not be the final answer in neuroprotection for brain injury and stroke, right now they appear to offer the best hope for an effective treatment that needs to be carefully considered and evaluated as a safe, easy-to administer and effective therapy.
DISCLOSURES Donald Stein received royalties from an Emory University licensing agreement with BHR Pharma related to research on progesterone as a therapeutic agent. Dr Stein has also received research funding from BHR. In addition, Donald Stein occasionally serves as consultant to BHR and receives compensation for these services. The terms of this arrangement have been reviewed and approved by Emory University, which receives the major share of any revenue in accordance with its conflict of interest policies.
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Sayeed I, Stein DG (2009) Progesterone as a neuroprotective factor in traumatic and ischemic brain injury. In: Neurotherapy, Vol. 175 (Verhaagen J, et al., eds), pp 219 –237. New York: Elsevier. Schneier AJ, Shields BJ, Hostetler SG, Xiang H, Smith GA (2006) Incidence of pediatric traumatic brain injury and associated hospital resource utilization in the United States. Pediatrics 118:483– 492. Schumacher M, Guennoun R, Stein DG, De Nicola AF (2007) Progesterone: therapeutic opportunities for neuroprotection and myelin repair. Pharmacol Ther 116:77–106. Schumacher M, Robel P, Baulieu EE (1996) Development and regeneration of the nervous system: a role for neurosteroids. Dev Neurosci 18:6 –21. Schumacher M, Sitruk-Ware R, De Nicola AF (2008) Progesterone and progestins: neuroprotection and myelin repair. Curr Opin Pharmacol 8:740 –746. Shohami E, Gati I, Beit-Yannai E, Trembovler V, Kohen R (1999) Closed head injury in the rat induces whole body oxidative stress: overall reducing antioxidant profile. J Neurotrauma 16:365–376. Stein DG, Hoffman SW (2003) Estrogen and progesterone as neuroprotective agents in the treatment of acute brain injuries. Pediatr Rehabil 6:13–22. Stein DG, Hurn PD (2009) Effects of sex steroids on damaged neural systems. In: Hormones, brain and behavior, Vol. 4 (Pfaff DWD., et al., eds), pp 2223–2258. Oxford: Elsevier. Temkin NR, Anderson GD, Winn HR, Ellenbogen RG, Britz GW, Schuster J, Lucas T, Newell DW, Mansfield PN, Machamer JE, Barber J, Dikmen SS (2007) Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial. Lancet Neurol 6:29–38. Toung TJ, Chen TY, Littleton-Kearney MT, Hurn PD, Murphy SJ (2004) Effects of combined estrogen and progesterone on brain infarction in reproductively senescent female rats. J Cereb Blood Flow Metab 24:1160 –1166. University of California—Davis (2010) UC Davis to study drug therapy to minimize death and disability from traumatic brain injury. [press release]. http://ucdmc.ucdavis.edu/welcome.features/20100203_ brain_injury/index.html. Utagawa A, Truettner JS, Dietrich WD, Bramlett HM (2008) Systemic inflammation exacerbates behavioral and histopathological consequences of isolated traumatic brain injury in rats. Exp Neurol 211:283–291. Vilalta A, Sahuquillo J, Rosell A, Poca MA, Riveiro M, Montaner J (2008) Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. Intensive Care Med 34:1384 –1392. Vink R, Nimmo AJ (2009) Multifunctional drugs for head injury. Neurotherapeutics 6:28 – 42. Vink R, Van Den Heuvel C (2004) Recent advances in the development of multifactorial therapies for the treatment of traumatic brain injury. Expert Opin Investig Drugs 13:1263–1274. Watson NF, Barber JK, Doherty MJ, Miller JW, Temkin NR (2004) Does glucocorticoid administration prevent late seizures after head injury? Epilepsia 45:690 – 694. Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG (2007) ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med 49:391–402. Xiao G, Wei J, Yan W, Wang W, Lu Z (2008) Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care 12:R61. Xiong Y, Mahmood A, Chopp M (2009) Emerging treatments for traumatic brain injury. Expert Opin Emerg Drugs 14:67– 84. Zhou ML, Zhu L, Wang J, Hang CH, Shi JX (2007) The inflammation in the gut after experimental subarachnoid hemorrhage. J Surg Res 137:103–108.
(Accepted 6 April 2011) (Available online 14 April 2011)
REVIEW PROGESTERONE IN THE TREATMENT OF ACUTE TRAUMATIC BRAIN INJURY: A CLINICAL PERSPECTIVE AND UPDATE D. G. STEIN*
BACKGROUND: TRAUMATIC BRAIN INJURY IS A SERIOUS PUBLIC HEALTH CONCERN
Brain Research Laboratory, Department of Emergency Medicine, Emory University, 1365 B Clifton Road NE, Suite 5100, Atlanta, GA 30322, USA
In the United States, civilian traumatic brain injury (TBI) is by far the most common cause of death in men under the age of 35. It is also a major problem in the elderly, among whom falls contribute to head injury, which then leads to increased morbidity and risk of death. Many people do not know that TBI is also a major factor in morbidity and disability and a leading cause of death in children, resulting in 7400 deaths, more than 60,000 hospitalizations, and over 600,000 Emergency Department visits annually in the US alone (Centers for Disease Control and Prevention, 2010). Pediatric TBI can cause developmental impairments and life-long disability. Over 300,000 pediatric head injuries result from contact sports and can have long-term consequences even though the initial injuries are often said to be “minor” or “mild” (Schneier et al., 2006). TBI has been getting increased public attention in the US, at least in part because of the large number of concussive blast injuries suffered in the Iraq and Afghanistan conflicts. US government sources indicate that, from 2003 to 2007, as many as 43,779 surviving combat casualties were diagnosed with varying degrees of brain injury caused by explosive devices (Ippolito, 2007), and there have been suggestions in the national press that even these numbers are under-reported. As of this writing, no new pharmacotherapy for TBI has entered general clinical practice since the National Institutes of Health (NIH) began profiling articles in this field. Glucocorticoids such as dexamethasone, once the gold standard for TBI treatment, are now considered detrimental to central nervous system (CNS) repair (Alderson and Roberts, 2000; Vink and Van Den Heuvel, 2004; Watson et al., 2004; Gomes et al., 2005). The Corticosteroids after Significant Head Injury (CRASH) trial, with more than 10,000 subjects in 40 countries, was stopped when it was found that the treatment group had a significantly higher mortality rate than the control group (Roberts et al., 2004; Edwards et al., 2005). More recently, an NIH-funded clinical trial of magnesium sulfate was terminated for the same reason (see Temkin et al., 2007 for details). Cyclosporine, an immunosuppressive drug in clinical use, has exhibited neuroprotective properties in animal models of TBI (Vink and Nimmo, 2009; Xiong et al., 2009), where it appears to work by preserving mitochondrial metabolism and function. Cyclosporine has been tested in a single-center, 40-patient, randomized, double-blind trial for
Abstract—Despite decades of laboratory research and clinical trials, a safe and effective treatment for traumatic brain injury has yet to reach clinical practice. The failure is due in part to the prevalence of a reductionist philosophy and research praxis that targets a single receptor mechanism, gene, or brain locus. This approach fails to account for the fact that traumatic brain injury is a very complex disease caused by a cascade of systemic toxic events in the brain and throughout the body. Attention is now turning to pleiotropic drugs that act on multiple genomic, proteomic, and metabolic pathways to enhance morphological and functional outcomes after brain injury. Of the agents now in clinical trial, the neurosteroid progesterone appears to hold considerable promise. Many still assume that progesterone is “just a female hormone” with limited, if any, neuroprotective properties, but this view is outdated. This review will survey the evidence that progesterone has salient pleiotropic properties as a neuroprotective agent in a variety of central nervous system injury models. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. © 2011 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: progesterone, neuroprotection, traumatic brain injury, neurosteroid, clinical trials, pharmacotherapy. Contents Background: traumatic brain injury is a serious public health concern 101 Why has it been so hard to find a treatment for brain injury? 102 Is progesterone a good candidate for TBI pharmacotherapy?102 Why is progesterone more likely to succeed as a treatment? 102 Progesterone phase II clinical trials 103 Despite the promising results thus far, questions remain 103 Progesterone is now in Phase III clinical trials 104 There are still questions about PROG’S effectiveness 104 Conclusions 105 Disclosures 105 References 105 *Tel: ⫹1-404-712-9704; fax: ⫹1-404-727-2388. E-mail address: [email protected] (D. G. Stein). Abbreviations: CNS, central nervous system; DRS, Disability Rating Scale; GOS, Glasgow Outcome Scale; GSC, Glasgow Coma Scale; HRT, hormone replacement therapies; MPA, medroxyprogesterone acetate; NIH, National Institutes of Health; PROG, progesterone; TBI, traumatic brain injury.
0306-4522/11 $ - see front matter © 2011 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2011.04.013
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dosing and safety (Hatton et al., 2008) in patients with severe TBI. Although it has only a 4-h window for treatment, and mortality rates were not reduced, the drug appeared to be well-tolerated and did lead to somewhat better functional outcomes in patients surviving up to and past 6 months post-injury. At present, it is not certain that a Phase III trial will proceed. Other drugs now in Phase I or Phase II studies for safety and preliminary evidence of efficacy include erythropoietin, a hormone which stimulates the formation of red blood cells and has been shown to have neuroprotective properties in animal TBI models; darbepoetin (Aranesp™) (Grasso et al., 2009; Mammis et al., 2009), a modified form of erythropoietin used in the treatment of anemia in dialysis patients which reduces oxidative stress in injured brain tissue; Premarin™, a commercial form of conjugated equine estrogens; methylphenidate, an amphetamine-like drug used to treat attention deficit disorder; and hypotonic saline for the treatment of intracranial hypertension. A randomized, double-blind trial (close to 200 patients) for Citicoline, an acetylcholinesterase inhibitor sold as a food supplement and thought to enhance cognitive performance in Alzheimer’s patients, is in progress. A previous Phase III trial using this agent to treat ischemic stroke did not provide any evidence of efficacy compared to controls (Clark et al., 2001). Several forms of human growth hormone such as NNZ-2566 are being tested in an industrysponsored multi-center trial. Recent trials with Genotropin™ and Somatotropin™ have been withdrawn.
WHY HAS IT BEEN SO HARD TO FIND A TREATMENT FOR BRAIN INJURY? TBI is a complex systemic disorder. When the brain is injured, the physiology of the entire organism changes. This means that very often, the consequences of a “brain injury” are not limited to the brain itself. Disregarding the complexity of TBI, biomedical researchers often focus on developing a drug with a limited, specific mechanism of action—for example, an agent that acts on a single neurotransmitter (e.g. acetylcholine, gamma-Aminobutyric acid (GABA)), or binds primarily or exclusively to a specific receptor (e.g. N-methyl-D-aspartic acid (NMDA)), in the expectation that blocking the channel will prevent excessive calcium influx leading to cell death in the brain and that all will be well thereafter. This approach fails to address acute simultaneous changes produced by the TBI in other organs such as the gut, spleen, thymus, and liver. All these changes create a further cascade of injury that can contribute to the brain injury syndrome. Many physiological processes can be affected by a brain injury. More than 10 years ago Shohami et al. (Shohami et al., 1999) reported that closed head injury can produce oxidative stress reactions in heart, kidney, lung, liver, and other body tissues in the first 24 h after injury. In another study (Glantz et al., 2005), transient ischemia produced by middle cerebral artery occlusion followed by reperfusion reduced anti-oxidant reserves in brain and peripheral organs such as the heart, liver, and
lung, suggesting that after a stroke, the whole body is subjected to oxidative stress. In several other reports, ischemic stroke has been shown to produce a dramatic reduction in the size of the spleen and thymus gland within hours after the injury (Offner et al., 2006). A number of studies (Hang et al., 2005, 2007; Chen et al., 2007; Zhou et al., 2007) report similar findings—that brain injuries can induce marked expression of inflammatory factors like tumor necrosis factor-alpha (TNF-␣) or nuclear factor-kappa B (NF-B) and interleukin-6 (IL-6) in the intestinal mucosa of the gut. The complex nature of these systemic inflammatory problems is more obvious in patients with moderate to severe TBI, but both the human and animal literatures suggest that multiple organ injury/dysfunction can manifest itself even when an injury is relatively mild (Utagawa et al., 2008; Vilalta et al., 2008). Given what we now know about the progression of a brain injury in trauma or stroke, there is an urgent need for an agent that works at multiple levels of injury, on a variety of receptors that inhibit the destructive cascade of events following TBI, and that stimulates the tropic and trophic events needed to enhance repair and regenerative processes.
IS PROGESTERONE A GOOD CANDIDATE FOR TBI PHARMACOTHERAPY? Hidden in plain sight, the hormone progesterone (PROG) may be the pleiotropic drug that can markedly attenuate the complex injury cascade associated with TBI. After more than two decades of pre-clinical research on the use of PROG in TBI, it is clear that this neurosteroid has many complex properties affecting the mechanisms involved in neuroprotection and repair after various kinds of CNS injury (Sayeed and Stein, 2009; Stein and Hurn, 2009). There are currently more than 180 articles showing the neuroprotective effects of PROG from more than two dozen laboratories, using four species including humans and 22 different models of injury. Much of this work has been recently reviewed (Toung et al., 2004; Cutler et al., 2005; Fee et al., 2007; Schumacher et al., 2007; Sayeed and Stein, 2009; Stein and Hurn, 2009; Vink and Nimmo, 2009). Why is progesterone more likely to succeed as a treatment? PROG’s effectiveness as a neuroprotective agent is probably related to its protective properties for both males and females during development, when the fetus of both sexes is exposed to high levels of maternal PROG during almost the entire period of gestation. Many of the processes involved in CNS repair after brain injury are thought to recapitulate what takes place in normal brain development (see Stein and Hoffman, 2003 for review). PROG is synthesized by oligodendrocytes and in excitatory neurons in the brains of both males and females in roughly equal amounts (Baulieu and Robel, 1990; Baulieu, 1991; Schumacher et al.,
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1996; Baulieu et al., 2001). Hirst and colleagues (Hirst et al., 2009) point out that in many species including humans, PROG and allopregnanolone play a role in reducing excessive excitotoxicity and inflammation while maintaining normal levels of cell proliferation and apoptosis in the developing brain. During development much of the circulating PROG comes from the placenta, but because they found that PROG is synthesized in the CNS, Baulieu and his colleagues were the first to recognize it as a true neurosteroid (Baulieu and Robel, 1990; Baulieu, 1991; Stein and Hoffman, 2003) that can play a key role in sustaining levels of myelin in some types of neurodegenerative disorders (Schumacher et al., 2008; De Nicola et al., 2009; Labombarda et al., 2009; Leitner, 2010). Keeping in mind that PROG is a pleiotropic developmental (“pro-gestational”) hormone will help us to understand why it has promise as a treatment for brain injury in adults (Kelleher et al., 2011). Progesterone phase II clinical trials Two independent Phase II clinical trials have now shown evidence of PROG’s promise for the treatment of acute TBI. ProTECT I (Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment) was a National Institutes of Neurological Disorders and Stroke-supported, randomized, double-blind, placebo-controlled trial of 100 patients suffering from moderate to severe brain injury (Glasgow Coma Scale (GSC) scores of 4 –12) (Wright et al., 2007). In the single center study the primary aim was to determine the safety of the PROG infusion; a secondary aim was to gather preliminary evidence of beneficial effect. Exposure to the hormone treatment was optimized with a four PROG to one placebo randomization design. Seventy-three percent of the study patients were males. Approximately 76% of the patients had blunt head trauma resulting from automobile accidents. Patients enrolled in the study were admitted only with proxy consent. On average, obtaining consent took about 6 h after admittance, meaning that the treatment was delayed for at least 6 h after the TBI. The group that was given PROG was started on an i.v. drip of 0.71 mg/kg/h for the first hour which was then reduced to 0.50 mg/kg/h for the next 71 h. A Data Safety Monitoring Board found no serious adverse events attributed to the PROG treatment. Patients in the PROG group remained in a coma longer, but demonstrated more than a 50% reduction in mortality at 30 days compared to the controls (P⬍0.06). The group diagnosed with moderate injuries showed significant “encouraging signs of improvement” on their Disability Rating Scale (DRS) outcome at 30 days compared to patients receiving placebo (P⬍0.02). The ProTECT I results were later supported by another single-center trial in China of 159 severely brain-injured subjects (GCS ⱕ8) (Xiao et al., 2008) which tracked patient outcomes for a longer period of up to 6 months following enrollment in the trial. In this 1:1 randomized, double-blind, placebo-controlled trial, the 82 subjects in the PROG group were treated beginning within 8 h of injury and continuing for 5 days with intramuscular injections of PROG (1.0 mg/kg)
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every 12 h. The PROG group had significantly better survival as well as functional outcomes at both 3 and 6 months than the 77 patients given placebo. A dichotomized analysis showed that at the 3-month follow-up, 47% of the PROGtreated patients showed better functional outcomes on the Glasgow Outcome Scale (GOS) compared to 31% of the placebo group (P⬍0.034). At the 6-month follow-up the results were similar, with favorable outcomes in 58% of the PROG group compared to 42% of the placebo group (P⬍0.048). The PROG group had 18% mortality at 6 months, while the placebo group had 32%. It is important to emphasize that in both clinical trials PROG not only appeared to reduce mortality, but also reduced morbidity and improved functional outcomes (Doppenberg et al., 2004). Recently, the Department of Defense has funded a Phase II trial at the University of California, Davis, using allopregnanolone to treat moderate to severe TBI. According to a UC-Davis press release, “Researchers hope to enroll 136 male and female patients to determine whether receiving the drug minimizes brain damage, reduces or eliminates post-traumatic epileptic seizures, and improves patients’ psychological functioning and overall quality of life” (University of California—Davis, 2010). The supply of allopregnanolone will be manufactured at the UC Davis Institute for Regenerative Cures’ Good Manufacturing Practices Facility. This will be the first clinical test of allopregnanolone for TBI and may prove to be a worthwhile comparison to PROG for safety and efficacy in a clinical TBI setting. The clinicaltrials.gov website does not yet show the trial protocols, so the dosing details are not publicly available. Despite the promising results thus far, questions remain Although the pre-clinical studies show much benefit of PROG treatment and the positive results of two human clinical trials are very promising, Phase III multicenter clinical trials are needed to definitively confirm the utility of PROG for the treatment of acute TBI. So many clinical trials for TBI and stroke have failed at the Phase II–III stage, there is still considerable pessimism that a natural hormone could be more successful than the best efforts of the pharmaceutical industry. The two Phase II trials of PROG were small, singlecenter studies with a primary focus on safety. The randomization of the ProTECT I trial was not 1:1, so there were only a small number of patients who did not get the hormone and could serve as a comparison; thus a small shift in outcomes in a few patients could have led to different, less positive results. Some would argue that a dichotomized GOS is a fairly insensitive predictor of outcome and that more detailed and long-term neuropsychological testing is needed to confirm efficacy. This is an important concern, and long-term follow-up studies over a decade or more are unlikely in the present economic climate. The report from China also had some weaknesses, but it did have 1:1 randomization and they did get significant differences with a dichotomized GOS at 3 and 6 months after injury. Some experts expressed concern with the finding of a relatively high mortality rate in the placebo group. Thus, while providing grounds for opti-
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mism, the generalizability of the two Phase II trials needs to be confirmed in much larger trials—which are now underway. Progesterone is now in Phase III clinical trials An NIH-sponsored, Phase III, 31-center clinical trial for TBI is now underway across the United States. This is a 1:1 randomized, double-blind controlled trial which will examine 1140 patients. Treatment must begin within 4 h of injury in patients at least 18 years of age with a GCS score between 12 and 4. After a 1-h loading dose of 0.714 mg/kg intravenous, PROG or placebo is given by intravenous infusion at 0.5 mg/kg for 72 h, then tapered over an additional 24 h. The 4-h window of treatment is designed to optimize PROG’s neuroprotective effects by treating TBI patients as soon as possible. Food and Drug Administration approval for exemption from informed consent (EFIC) was granted for this purpose. The primary study end point is a stratified dichotomy of the GOS at 6 months. The trial will also track mortality, extent of adverse and serious adverse events, scores, and a number of other cognitive, neurological, and functional outcomes. More details can be found at http://clinicaltrials. gov/ct2/show/record/NCT00822900. In addition to the NIH study, BHR, a branch of Besins Pharma, a privately held Belgian/French pharmaceutical company, with the collaboration of the American Brain Injury Consortium (ABIC) and the European Brain Injury Consortium (EBIC), also recently began enrolling patients in a second clinical trial known as SyNAPSe. Approximately 1200 patients with severe (GCS scores of 4 – 8) closed-head TBI in whom treatment can be initiated within 8 h of injury will be enrolled in the study through 100 –120 medical centers in the United States, Western Europe, Israel, Singapore, and China. Patients are being randomized to receive a 5-day continuous i.v. infusion of PROG or placebo in a 1:1 allocation and followed for 6 months. The GOS is the primary study end point. For more information see http://www.synapse-trial.com/.
THERE ARE STILL QUESTIONS ABOUT PROG’S EFFECTIVENESS Despite the positive findings, some still argue that the results of PROG neuroprotection studies sound too good to be true for a hormonal agent that has always been under our noses (Loane and Faden, 2010 and Gibson et al., 2008). Another source of skepticism is that recent hormone replacement therapies (HRT) in post-menopausal women have been disappointing, and HRT clinical trial results led to a general concern that PROG might have no benefits or even detrimental effects. The trials were designed to use the most commonly prescribed hormones given to women in the United States. These agents were synthetic (conjugated equine estrogens combined with the progestin medroxyprogesterone acetate (MPA) and did not mimic the physiological effects of native PROG or 1--estradiol or estrone—the hormones that women naturally make. The synthetic HRT trial agents were given over long periods of time, whereas in the TBI trials, PROG treatment was administered only for 5 days post-injury
and were thus not directly comparable. From a clinical perspective, one serious area of concern is the fact that progestins are not identical to PROG in terms of how they interact with intranuclear and membrane receptor mechanisms (Ciriza et al., 2006; Jodhka et al., 2009). Thus, they should not be confused or used interchangeably in the treatment of TBI or other CNS disorders in the absence of careful evaluation for safety and efficacy. This is not a minor issue and has had serious impact for women on hormone therapy (Bethea, 2011). For example, some progestins can increase the proliferation of embryonic progenitor cells, while others such as MPA (used in the HRT trials) inhibited proliferation (Liu et al., 2010). Nilsen et al. (Nilsen et al., 2006) found that MPA exacerbated glutamate excitotoxicity in hippocampal neurons whereas native PROG protected against glutamate damage. These findings were replicated by Kaur et al. (Kaur et al., 2007), who showed that PROG protected cerebral cortical explant tissue from glutamate poisoning while MPA did not. This group showed that PROG potentially conferred neuroprotection by significantly upregulating the expression of brain-derived neurotrophic factor (BDNF), but MPA had no such effects. In fact, MPA was also recently shown to block brain mitochondrial respiration and function (Irwin et al., 2011). What we have learned from these studies is that long-term use of synthetic hormones that may mimic some, but not all of the effects of natural PROG and estrogen can have bad outcomes. While there has been considerable confirmation of the neuroprotective effects of PROG treatment after CNS injury, three recent studies have shown no positive effects after treatment with PROG. Fee et al. (Fee et al., 2007) reported no benefits of PROG after spinal cord contusion injury and 5 or 14 days of treatment, but they did see some evidence of gray-matter neuronal sparing in the 14-day treatment groups. In a stroke study, Toung et al. (Toung et al., 2004) gave senescent female rats high doses of PROG for almost 3 weeks before ischemic stroke and then abruptly terminated treatment in the post-ischemic period. No beneficial effects following this kind of treatment regime were observed, but this could be due to the age of the subjects and the triggering of PROG withdrawal syndrome in the older animals. The failure to observe a positive outcome may have been prevented by gradual tapering off of the dose (see Cutler et al., 2005 for a discussion of this issue). Gilmer et al. (Gilmer et al., 2008) created a “moderate” unilateral contusion of parietal cortex in rats and found no beneficial effects after 3 days of PROG treatment. These authors suggest that PROG might work in some injury models but not all, clearly a real possibility that can only be confirmed by further pre-clinical research. However, the broader literature does not appear to support the contention that PROG treatment for brain injury is a failed approach. In addition, two recent reviews (Gibson et al., 2008; Loane and Faden, 2010) speculate that most, if not all, preclinical studies testing neuroprotective agents, including PROG, fail to meet their criteria for pre-clinical drug development. However, despite legitimate concerns, given the large number of studies using PROG, most, if not all, of the criteria
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stipulated in the reviews by Loane and Faden, and Gibson et al. have been addressed for this agent. Studies for most of the other neuroprotective agents cited in the Loane and Faden paper may meet fewer of their criteria. However, even if all the criteria were indeed met for the animal studies, there is still no guarantee that a completely successful agent for brain repair would be discovered until large clinical trials can be conducted and evaluated.
CONCLUSIONS In over 180 pre-clinical studies, PROG or its metabolites have demonstrated neuroprotective properties in a variety of brain injury models. It is now well-documented that neurosteroids have neurotrophic, anti-inflammatory and anti-apoptotic properties, all of which contribute to reducing extent of injury and preserving neural and vascular integrity early in the injury cascade that inevitably accompanies TBI. In two preliminary clinical studies, PROG was effective in reducing mortality and improving functional outcomes when measured 30 days 3 months, and 6 months after injury. The PROG treatments were not associated with any serious adverse events. The pathologic events associated with loss of brain tissue over time are complex and heterogeneous. TBI is not a localized event implicating only neural tissue. These systemic and organismic changes result in a state of polytrauma and frailty if not corrected in the early stages of the injury. Given the complexity of the disease, a reductionistic approach to drug development that seeks a single receptor or signaling pathway or set of genes to account for the patient’s illness and recovery will explain neither the disease nor the recovery process. Given all the clinical trial disappointments to date, some healthy skepticism about PROG’s benefits is warranted, but there is still a critical need to find a safe, easy-to-administer agent with pleiotropic properties that can work at multiple levels to address the complex and systemic disruptions produced by TBI, and perhaps stroke and some neurodegenerative disorders. PROG, with its multiple anti-inflammatory, anti-apoptotic, and trophic growth-promoting properties, is essentially a developmental hormone, evolved to protect both the male and female fetus during gestation. Although PROG and its metabolites may not be the final answer in neuroprotection for brain injury and stroke, right now they appear to offer the best hope for an effective treatment that needs to be carefully considered and evaluated as a safe, easy-to administer and effective therapy.
DISCLOSURES Donald Stein received royalties from an Emory University licensing agreement with BHR Pharma related to research on progesterone as a therapeutic agent. Dr Stein has also received research funding from BHR. In addition, Donald Stein occasionally serves as consultant to BHR and receives compensation for these services. The terms of this arrangement have been reviewed and approved by Emory University, which receives the major share of any revenue in accordance with its conflict of interest policies.
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(Accepted 6 April 2011) (Available online 14 April 2011)