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Perspective New Treatments in the Horizon for Traumatic Brain Injuries

BY IN health & wellness On 03-10-2016

Milos Cekic; Donald G. Stein
Future Neurology. 2010;5(1):3746.

Abstract and Background

Abstract

Traumatic brain injury is a significant clinical problem for which there is still no effective treatment. Recent laboratory and clinical data demonstrate a potentially beneficial role for neurosteroids, such as progesterone and allopregnanolone, in the treatment of traumatic brain injury, ischemic stroke and some neurodegenerative disorders. Unlike single­target agents, progesterone affects many of the molecular and physiological processes in the cascade of secondary damage after a traumatic brain injury. This article updates a 2006 Future Neurology review of the research on progesterone and its metabolites in the treatment of traumatic brain injury, and presents new evidence that vitamin D deficiency can reduce progesterone neuroprotection, while combining progesterone with vitamin D produces better functional outcomes after TBI compared with eithertreatment alone.

Background

When our review of the role of progesterone (PROG) in brain injury was published in Future Neurology in 2006, there was no clinically available treatment for traumatic brain injury (TBI). [1] This is still the case today. TBI is a major clinical concern in the USA and worldwide, and has been receiving increased public attention (and more funding) partly owing to the large number of concussive blast injuries suffered in the conflicts in Iraq and Afghanistan. US government sources indicate that, from 2003 to 2007, as many as 43,779 surviving combat casualties have been diagnosed with varying degrees of brain injury caused by explosive devices.[101] Taken together with more than 1.5 million annual cases of TBI occurring in the USA alone (including 300,000 annual sports­related injuries in children and young adults), [102] it is evident that brain injury continues to represent a substantial clinical and social problem.

Despite these grim data, there are grounds for optimism. Two independent Phase II clinical trials have now reported that PROG can be administered with a delay of up to 6 h or more after injury and still show beneficial results. The Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (ProTECT) trial was a randomized, double­blind, placebo­controlled trial with 100 patients suffering from moderate­to­severe brain injury (Glasgow Coma Scale [GSC] scores of 4­12). [2] The patients treated with PROG were started on an intravenous (iv.) drip of 0.71 mg/kg at 14ml/h for the first hour, reduced to 0.50 mg/kg at 10 ml/h for the next 11 h. Five additional 10­h infusions at 10 ml/h were administered for the remainder of the 3 days of treatment. No serious adverse events were noted, and patients with severe injuries receiving 3 days of iv. PROG starting within 6­8 h after injury demonstrated a more than 50% reduction in mortality at 30 days compared with controls. The group with moderate injuries also showed significant ‘encouraging signs of improvement’ on their Disability Rating Scale (DRS) outcomes at 30 days compared with patients receiving placebo. The researchers concluded that PROG was beneficial for patients with both severe and moderate injuries, although the results were somewhat confounded in the severely injured by the fact that many in the group administered PROG survived who would not have otherwise survived without the treatment.

The ProTECT trial results were supported by another single­center trial of 159 severely brain­injured subjects (GCS score ≤ 8) [3] that tracked patient outcomes for a longer period. The 82 subjects in the PROG group were treated for 5 days with intramuscular injections of PROG (1.0 mg/kg intramuscularly every 12 h for a total of 5 days) started within 8 h of injury and demonstrated significantly better survival as well as functional outcomes at both 3 and 6 months compared with the 77 patients given placebo.

A dichotomized analysis demonstrated that at the 3­month follow­up, 47% of the PROG­treated patients showed better functional outcomes on the GCS compared with 31% of the placebo group. At the 6­month follow­up the results were similar, with favorable outcomes in 58% of the PROG group compared with 42% of the placebo group. The PROG group had 18% mortality at 6 months, while the placebo group had 32% mortality at 6 months. It is important to emphasize that in both clinical trials PROG not only reduced mortality, but also significantly improved functional outcomes. Although these reports need to be confirmed in larger multicenter trials, these two trials are the first pharmacological intervention for TBI to show a substantial
benefit in human patients. [4]

Based on these promising findings, the NIH is funding a national Phase III multicenter trial to test PROG in over 1000 moderately to severely brain ­injured patients. This trial, termed ProTECT III, is designed to determine the efficacy of Progesterone Treatment for Brain Injury: An Update Milos Cekic; Donald G. Stein Future Neurology. 2010;5(1):37­46. administering iv. PROG (initiated within 4 h of injury and administered for 72 h, followed by an additional 24­h taper) versus placebo for treating victims of moderate ­to ­severe acute TBI (GCS score of 12­4). The trial will track mortality, number of adverse and serious adverse events, DRS, and cognitive, neurological and functional outcomes.

Since the publication of the successful Phase II trials in 2007­2008, [2,3] there has been more interest in determining the extent to which PROG and some of its metabolites can enhance neuroprotection after different kinds of CNS injury. From just a few studies beginning in the 1990s, there are now over 100 published preclinical studies from 25 different laboratories, using four different species in 22 different injury models, demonstrating that PROG and its metabolites may be highly neuroprotective.

Many of these studies have been published within the last few years.

Here we summarize recent findings illuminating some of the neuroprotective mechanisms of PROG and some of its metabolites.

Further details can be found in extensive reviews by Brinton et al., [5] Schumacher et al., [6] Singh et al., [7] Stein and Hurn [8] and Stein. [9] The earlier literature on PROG focused mainly on the phenomenological markers of CNS repair so that, for example, if administered after a TBI, the hormone was shown to reduce cerebral edema, re­establish the compromised BBB, improve vascular tone, downregulate the expression of inflammatory factors, reduce excitotoxic damage and prevent post­traumatic seizures. [5­10] As these positive studies began to accumulate, attention turned to the question of how PROG was exerting its effects at the molecular level (whether this occurred through the classical PROG receptor or through other pathways).

Update on Progesterone & Recovery from Brain Injury: Mechanisms & Systems

Overview

Over two decades ago it was first noted that female rats show better recovery of cognitive function than their male counterparts after bilateral damage to the medial frontal cortex (MFC). This effect was then found to vary with hormonal cycles and was due to endogenous levels of PROG, which in turn suggested the possibility of using exogenously administered PROG in order to improve recovery in both males and females. [11] Since then, the effectiveness of PROG treatment in functional recovery after TBI has been repeatedly demonstrated, [5,6,9,12,13] with most of the work focusing on the mechanisms of action. We now believe that the neuroprotective efficacy of PROG is a result of its actions on multiple genomic, proteomic and receptor systems, rather
than on a single mechanism. It has now also become more clearly established that moderate and severe TBI cause systemic injuries that alter metabolic and physiological functions throughout the body; [14] an effective treatment should therefore have systemic effects.

Molecular Effects of Progesterone

A significant problem with damage to the CNS is disruption of blood flow to the local area of injury, resulting in loss of oxygen and glucose, energy failure and, ultimately, cell death. PROG has been demonstrated to protect neurons from ischemia and to decrease the size of the damaged area.  [8,15] This resistance to injury is probably owing to several protective mechanisms, including maintenance of mitochondrial function, increased prosurvival signaling and reduced proapoptotic signaling. [6,16­21]

PROG affects mitochondria in multiple ways. It helps restore them to normal morphology even after they have undergone severe vacuolation, [22] inhibits the release of proapoptotic cytochrome c, [23,24] and reduces the levels of proapoptotic B­cell lymphoma (Bcl)­2­associated X protein (Bax), Bcl­2­associated death­promoter (BAD) and activated caspase­3. [25­27] PROG also upregulates the expression of antiapoptotic mitochondrial proteins such as Bcl­2. PROG may affect the expression of these mitochondrial proteins through activation of the ERK signaling pathway, which phosphorylates the cAMP response element binding protein (CREB), upregulates Bcl­2, and is known to provide improved resistance to ischemia. [5] PROG and its metabolites have also been demonstrated to modulate MAPK and PI3K signaling in the hippocampus, hypothalamus and cerebellum of ovariectomized rats in vivo. [28,29] Furthermore, PROG has been demonstrated to reverse alterations in mitochondrial respiration [30] and to normalize the expression of Na+,K+-ATPase in experimental autoimmune encephalomyelitis and models of nerve and spinal cord crush injury. [31­33] Since both respiration and Na +,K+-ATPase are important components in the cascade that leads to energy failure and loss of ionic gradients, we believe that this regulation of cellular metabolism is a key step in the prevention of cell death and the attenuation of secondary injury.

PROG has also been demonstrated to reduce inflammation, a significant mechanism of secondary injury, and is known to reduce microglial activation, as well as production of proinflammatory cytokines such as TNF­α and IL­1. [9,34] This reduced inflammatory response is not only beneficial in the injury penumbra but has significant systemic effects, since TBI­ associated systemic inflammation can often lead to multiorgan failure and infection [13] (mechanisms that are, in addition to cerebral edema, a frequent proximal cause of death after brain injury). Similar findings have been reported by Pan and colleagues, who found that following TBI in rats, expression of NF­κβ, p65 and TNF­α were markedly decreased if the animals were administered PROG injections soon after the injury. [35] Measurement of brain edema, lesion volume and behavioral outcomes also revealed that PROG was effective in reducing the severity of the damage. Furthermore, in a series of studies, Chen et al. demonstrated that treatment with PROG reduces the expression of inflammatory cytokines, not just in the damaged brain, but also systemically in non­neuronal tissue such as the gut, spleen and intestine. [17,36­38] These findings support the systemic nature of brain injury and the fact that PROG acts at multiple receptor sites to control inflammation and improve functional outcomes (see also [39,40]).

Furthermore, there is evidence that PROG treatment after TBI reduces lipid peroxidation. The mechanisms of this action are not completely understood, [6] but it is thought to occur in the upregulation of antioxidant enzymes such as superoxide dismutase.[41] Reducing the damage caused by reactive oxygen species and nitrogen species is known to improve cell survival in the penumbra of the injury by maintaining membrane integrity, and also helps to maintain the BBB by limiting oxidative damage to the capillary endothelium. PROG also helps maintain BBB function by upregulating P­glycoprotein, an efflux pump transporter and marker of BBB health that serves to eliminate xenobiotic and toxic substances, which consist of inflammatory cytokines and reactive oxygen species­producing compounds in the case of traumatic injury. [42]

These molecular mechanisms ­ decreased inflammation and lipid peroxidation, maintenance of BBB integrity and improved ionic stability ­ all help to reduce cerebral edema after TBI. [6] Recent findings also indicate that PROG regulates the expression of aquaporin­4, a water channel expressed in astrocyte endfeet that is thought to be important for the development of edema.
[43] Since brain swelling is one of the final neurological causes of mortality after TBI, this is an important concern for the clinical management of patients with brain injury.

Summary of Progesterone Effects on Receptors

Although many of the molecular effects of PROG in neuroprotection have been described, it is still not known whether the classical intranuclear receptors are responsible for all of the hormone’s effects. In this review and others, perhaps contrary to the opinions of colleagues convinced that PROG can act only at a single receptor site, we have stressed the hypothesis that PROG has multiple beneficial effects that cannot be attributed solely to the PROG intranuclear receptor. For example, VanLandingham et al. have demonstrated that the enantiomer of PROG can substantially reduce cerebral edema following TBI without being able to bind to PROG receptor. [44] PROG and its metabolites, such as allopreganolone, can reduce excitotoxicity at the NMDA receptor [45] and possibly decrease the incidence and severity of post­traumatic epilepsy by acting to potentiate γ­aminobutyric acid type A (GABAA) receptors to release more inhibitory neurotransmitters, thus acting, in some respects, similar to barbiturates and other anesthetics (e.g., see [39] ). Studies in PROG receptor­knockout mice have demonstrated that the hormone can still exert anxiolytic and anesthetic effects, even in the absence of the PROG receptor. This probably occurs through the hormone’s metabolism to allopregnanolone and its actions on the GABAA and σ­1 receptors. [46­-48]

Covey and associates have published excellent and detailed reviews describing how neurosteroids interact with the GABAA receptor sites [49] (see [50] for more detail). With regard to mediating inflammatory reactions, PROG utilizes the glucocorticoid and PROG receptors to inhibit the production of nitrite and cytokines, such as IL­12, whereas synthetic progestins do not have this effect. [51] After brain injury, it also appears that PROG can modulate the activation of Toll­like receptors, which in turn affect the expression of inflammatory signaling factors, such as NF­κβ and other proinflammatory cytokines. [36] In neuroprotection, intracellular calcium regulation and homeostasis are important for cell survival after injury. Hwang et al. found that PROG influences the activity of inositol 1,4,5­trisphosphate receptors, which in turn regulate the levels of intracellular calcium in cultures of primary hippocampal neurons. [52] Some researchers argue that PROG can have both inhibitory and excitatory actions depending on whether the hormone is acting in the peripheral nervous system or CNS. For instance, Viero and Dayanithi demonstrated that PROG could produce substantial calcium influx by activating GABAA and oxytocin receptors in the hypothalamus and supraoptic nucleus in neonatal rodents, but they observed the opposite effects in embryonic dorsal root ganglion, where GABA inhibited calcium influx. [53] The very rapid effects of PROG (such as its effects on inflammation and edema) are likely to be nongenomic and triggered at the cell surface. Recent experiments have identified a number of membrane PROG receptors, such as 25­Dx, or membrane PROG receptor­α, which when activated can stimulate the formation of new synapses and dendrites ­ important components of repair after CNS damage. [54] Guennoun et al. demonstrated that 25­ Dx expression is substantially increased in neurons and astrocytes after both spinal cord and brain injuries, whereas the classical intranuclear receptor was actually downregulated. [55] It is also interesting to note that the 25­Dx receptor is also very abundant in the hypothalamus, where growth hormone expression plays a role in CNS repair in response to cerebral injury.

From even this very cursory review of PROG receptor mechanisms, it is apparent that neurosteroid receptor mechanisms and their role in CNS repair are complex. It is well beyond the scope of this update to provide full details, but some excellent reviews are available. [5,21,56­58]

Progesterone in Aging & Brain Injury

Although TBI affects all age groups, it is an especially significant health problem for those aged over 70 years, where both the incidence of hospitalizations and mortality rates due to TBI are highest. [59] While deaths resulting from TBI have been reduced in most demographics with improvements in safety, they have increased significantly in the older population. The elderly are subject to physiological and metabolic alterations that can affect recovery after major trauma, and therefore need to be considered specifically with regard to both treatment modalities and characteristic underlying physiology.

Something New to Consider: Traumatic Brain Injury, Progesterone, Aging & Vitamin D Deficiency

In a recent study, our laboratory tested the effectiveness of PROG in attenuating the acute inflammatory response after TBI in aged rats. [42] We observed significantly reduced levels of inflammatory markers, such as TNF­α, IL­6, NF­κβ­p65 and COX­2, at 24, 48 and 72 h after injury. In addition, PROG reduced cell death, as measured by caspase­3 levels, and improved BBB integrity, as measured by P­glycoprotein levels. These molecular data were correlated with reduced cerebral edema and improved functional activity, all of which was consistent with the beneficial effects of PROG after TBI recorded repeatedly in younger animals. [17,25,26,30,35,36,37] The optimal doses and duration of treatment were also similar to those observed in younger animals, suggesting that PROG and its metabolites may be effective as a treatment for TBI across the life cycle.

In addition to advanced age itself, other factors that may affect the severity of TBI in the elderly include systemic issues, such as cardiovascular disease and atherosclerosis, hypertension, diabetes, kidney disease, cancer and hyperparathyroidism. [60] All these conditions can individually affect the response to injury, and each has also been recently associated with insufficient serum levels of vitamin D, [61,62] suggesting that vitamin D deficiency may pose a risk factor for TBI severity in the elderly. This is important since vitamin D deficiency has been noted in all segments of the population, but especially in the elderly [61] and hospitalized individuals. [63,64]

In another recent study, we examined the effects of vitamin D deficiency on acute inflammation in aged rats after TBI. [65] Our results demonstrated that, in both injured and uninjured aged rats, vitamin D deficiency can significantly elevate the levels of inflammatory markers (TNF­α, IL­1β, IL­6 and NF­κβ­p65), increase cell death and affect short­term behavior. This acute effect is important in translating these results to the human population since acute inflammation has been strongly linked to survival in human trauma patients. [66] Surprisingly, vitamin D deficiency also attenuated the beneficial effects of PROG administration after TBI, although it was possible to overcome this through coadministration with 1,25­dihydroxyvitamin D3 (VDH), the active form of vitamin D (Figure 1). Considering the prevalence of vitamin D deficiency in the elderly human population, these results could have significant consequences for clinical practice. They also suggest that treatments with multiple drugs that affect different mechanisms of CNS injury and repair may be effective in the management of TBI and other CNS disorders.

tbi-press-release-sept-2016

Effects of vitamin D deficiency on short­term behavior after traumatic brain injury. Locomotor behavior associated with acute inflammation in aged rats 72 h after TBI. The dark bars represent vitamin D­sufficient animals and the light bars represent vitamin D­deficient animals. It should be noted that only a combination of PROG (16 mg/kg) and VDH (5 µg/kg; D+PROG) returns behavior to sham­injured levels in deficient animals, whereas PROG alone is sufficient in nutritionally normal animals. This suggests that vitamin D deficiency exacerbates the injury and interferes with PROG treatment, but also that this effect can be reversed with acute VDH administration.

*p < 0.05 versus sufficient VH; ‡p < 0.05 versus deficient VH.
PROG: Progesterone; TBI: Traumatic brain injury; VDH: 1,25­dihydroxyvitamin D3
; VH: Vehicle­treated group.
Adapted with permission from [65].

Progesterone & Combination Therapies

The past two decades have seen the failure of many Phase II and III clinical trials for moderate and severe TBI, despite the fact that over 130 different compounds had initially shown promise in preclinical models of injury. [67] One of the major reasons suggested for this disappointing state of affairs is the fact that the complex and varied mechanisms observed in TBI cannot be adequately addressed by single­drug therapies targeted to a specific mechanism or receptor site. In contrast to the clear outcomes and well­circumscribed injuries of experimental animal models of injury, clinicians are well aware that human TBI pathophysiology is highly variable and heterogeneous, and affects many organs and tissue systems outside the brain itself.
There is growing recognition that pharmacotherapies targeting more than one mechanism, or the same mechanisms differently, or at different time­points, may be more effective than the commonly applied ‘monotherapies’. [67] This idea is already prevalent in the treatment of diseases such as HIV/AIDS and tuberculosis, where multitherapeutic approaches that target different parts of the disease process, act at different sites, and synergistically increase activity have become the standard. A similar approach has been suggested for TBI owing to its complex manifestation in human patients. [67] A number of treatments other than PROG have been suggested as the ‘main’ component of a potential combination therapy, including citicoline, erythropoietin, hypothermia, cyclosporin A, statins and hypertonic saline, [67] all of which have shown some promise in preclinical experiments. A literature review and our previous data with vitamin D deficiency suggest that VDH may also be a good candidate for combination therapy. [68] VDH is a neuroactive steroid known to be neuroprotective, with functional attributes similar to PROG, although it also has a number of divergent actions. It is also cheap, easy to administer and readily available. Based on our laboratory data, we think that a combination of PROG and VDH could lead to improved neuronal and cellular repair and recovery after injury, perhaps with less dosing and duration of treatment than with either agent administered alone.

A recent paper from our laboratory supports this approach. [69] We found that in cultured cortical neurons challenged with A recent paper from our laboratory supports this approach. [69] We found that in cultured cortical neurons challenged with glutamate, both VDH and PROG individually demonstrated neuroprotection, but combined treatment was more effective than treatment with either compound alone. Significantly, the most effective combination dosages were different from the individual ‘best’ doses, suggesting synergy between the two drugs that would not be predicted based on treatment with either agent alone.

tbi-press-release-sept-2016-2

Effects of combination progesterone and 1,25­dihydroxyvitamin D treatment on cell survival in vitro. The effects of progesterone and VDH combination treatment on glutamate­induced MTT reduction in rat primary cortical neurons. Cells were pretreated with different combinations of progesterone (20 µM) and VDH (doses shown as ‘D’ nM) for 24 h and subsequently exposed to glutamate (0.5 µM) for 24 h. Note the significant synergistic effect between P and D20, which is not observed with all combination dosages.

*p < 0.001 versus VH; ‡p < 0.001 versus CTRL; §p < 0.01 vesus P20 alone.
CTRL: Control; P: Progesterone; VDH: 1,25­dihydroxyvitamin D; VH: Vehicle.
Adapted with permission from [69].

One reason for treating injury pathways with multiple compounds is the possibility that a single repair mechanism may be modulated through different signaling mechanisms. Another reason is that a single high­dose drug treatment could saturate receptors and result in loss of functional benefit, which can happen in the case of PROG, for example. [70] This problem might be overcome by activating a different pathway leading to neuroprotection. [71] As an example, PROG and VDH could each increase the activity of γ­glutamyl transpeptidase by different mechanisms (PROG receptor­PROG activity and vitamin D receptor­VDH activity), resulting in higher overall antioxidant capacity. The possibility of amplifying a neuroprotective effect by combinatorial therapy is worth further exploration.

In summary, there is now substantial preclinical and clinical evidence that PROG can have salutary effects on morphological and functional recovery after TBI. Over the last 5­6 years and even since the first review of PROG in Future Neurology, much has been discovered about its specific mechanisms of repair. A comprehensive discussion of the many receptor mechanisms
involved in neurosteroid and vitamin D actions is beyond the scope of this update, but there are a number of recent articles on this subject.  [71-­76]  It is unfortunate that, thus far, most clinical trials for TBI treatments have failed, leading to considerable pessimism that a successful treatment will ever be found. Nonetheless, the fact that the NIH is supporting a Phase III multicenter trial using PROG for moderate­to­severe TBI is encouraging. [103] Unlike all other agents recently tested, PROG is a naturally trial using PROG for moderate­to­severe TBI is encouraging. [103] Unlike all other agents recently tested, PROG is a naturally occurring hormone with a high safety profile as demonstrated in two Phase II trials, both of which have shown substantial benefit in reducing mortality and improving functional outcomes after TBI. [2,3]

Future Perspective

As the Phase III trial goes forward, investigators and clinicians are asking: what’s next? One of the key clinical areas now under investigation in our laboratory is ischemic stroke. There is a small amount of literature demonstrating that in animal models of ischemic injury, PROG and its metabolite allopregnanolone can reduce the size of the ischemic infarct and produce functional benefits. [6] Less is known about PROG in the treatment of military blast injuries to the head and in pediatric traumatic or hypoxic brain injury, although these are also important potential applications. There is also growing interest in determining whether neurosteroids could be applied to more chronic neural disorders, such as amyotrophic lateral sclerosis, multiple sclerosis or Parkinson’s disease. This is certainly a topic for further review and discussion, but far too preliminary at this stage to consider for clinical trial.

A key point to keep in mind is that this hormone has characteristics that are protective of the fetus during gestation and of the nervous system when administered exogenously throughout the spectrum of development, including old age. It can be argued that PROG works as a neuroprotective agent because, to a great extent, many of the processes involved in brain repair are similar to growth and organizational processes occurring in early life. This notion is admittedly debatable, but it is a hypothesis that can be subjected to experimental testing and verification. If only because not much else in the field of brain injury has been shown to work as well, the hormone and its related metabolites deserve continued experimental attention and clinical evaluation.

Sidebar

Executive Summary

Background

  • Recent data demonstrates that neurosteroids, specifically progesterone (PROG) and some of its metabolites, are neuroprotective in experimental models of traumatic brain injury (TBI).
  • Two recent Phase II clinical trials of PROG as a treatment for TBI have also shown promise. A multicenter Phase III trial is now underway to determine clinical effectiveness.

Mechanisms & systems

  • PROG has been demonstrated to protect neurons from ischemic injury and to decrease the size of a lesion or ischemic infarct. These actions are a result of the hormone’s effects on maintenance of mitochondrial functions, increased prosurvival signaling, reduced inflammatory reactions, apoptosis and reactive oxygen species, stimulation of myelin synthesis and restoration of the BBB. These effects are systemic and not limited to the CNS injury itself.

Receptors

  • PROG acts at a number of different sites to enhance neuroprotection.
  • PROG and its metabolites can upregulate gene activity through their direct actions on the PROG intranuclear receptor, but they can also act at the NMDA receptor to reduce excitotoxicity and at the GABA A and σ­receptors to release more inhibitory neurotransmitters and thus block post­traumatic seizure activity.
  • PROG modulates Toll­like receptors, and this action affects the expression of inflammatory factors and cytokines such as NF­κβ and IL­1, among others.
  • The hormone also acts on membrane receptors, such as 25­Dx, which alters calcium toxicity.

Progesterone, aging & vitamin D

  • Vitamin D deficiency, especially in older subjects, leads to increased expression of inflammatory factors and reduces the benefits of PROG treatment for TBI. Combining vitamin D with PROG leads to better functional outcomes than either treatment alone.
  • Both PROG and vitamin D exert their effects through a variety of metabolic pathways and receptor mechanisms activated in the secondary injury cascade after TBI. Both can promote neural survival, repair and better functional outcomes.

Progesterone & combination therapies

  • Many clinical trials have failed because they do not address the complexity of TBI as a systemic disease and the varied mechanisms involved in tissue damage and repair. There is growing recognition that combination therapies, such as vitamin D and PROG, can have more beneficial effects in combination than when administered alone. This is a relatively new area of research that requires more attention.

Future perspective

  • The effects of neurosteroids on TBI may also prove beneficial in several other applications. In all cases, much work remains to be done:
    —Ischemic stroke: a few recent studies in animal models suggest that PROG and allopregnanolone can reduce infarct size and produce functional benefits;
    —Pediatric traumatic or hypoxic brain injury: some animal models are now being studied.
  • PROG’s effects on remyelination and inflammation may make it a therapeutic candidate for neurodegenerative and other chronic CNS disorders, such as amyotrophic lateral sclerosis, multiple sclerosis and Parkinson’s disease. This is a very new area where work has only just begun.

References

      1. Stein DG: Progesterone in the experimental treatment of central and peripheral nervous system injuries. Future Neurol. 1(4),429­438 (2006).
      2. Wright DW, Kellermann AL, Hertzberg VS et al.: ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann. Emerg. Med. 49,391­402 (2007).
        •• Along with, [3] presents results of Phase II trials using progesterone to treat moderate­to­severe traumatic brain injury (TBI).
      3. Xiao G, Wei J, Yan W, Wang W, Lu Z: Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit. Care 12,R61 (2008).
        •• Along with, [2] presents results of Phase II trials using progesterone to treat moderate­to­severe TBI.
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      5. Brinton RD, Thompson RF, Foy MR et al.: Progesterone receptors: form and function in brain. Front. Neuroendocrinol. 29,313­339 (2008).
        •• Excellent overview of progesterone receptor mechanisms in the CNS.
      6. Schumacher M, Guennoun R, Stein DG, De Nicola AF: Progesterone: therapeutic opportunities for neuroprotection and myelin repair. Pharmacol. Ther. 116,77­107 (2007).
        • Provides a detailed review of the potential uses of progesterone in the treatment of a spectrum of CNS disorders.
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        • Written for physicians wishing to learn more about progesterone in the treatment of TBI. This review includes a very brief overview of mechanisms of action.
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Websites

101. Ippolito CJ: Battlefield TBI: blast and aftermath. www.psychiatrictimes.com/display/article/10168/56916 (Accessed
October 2009)
102. Centers for Disease Control: What is traumatic brain injury. www.cdc.gov/ncipc/tbi/TBI.htm (Accessed September
2009)
103. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT00822900?term=progesterone,+TBI&rank=1

Papers of special note have been highlighted as:
• of interest
•• of considerable interest

Financial & competing interests disclosure

Portions of the research described in this manuscript were supported by NIH grants 5R01HD061971 and 5R01NS048451. Donald Stein is entitled to royalties from products of BHR Pharma related to the research described in this presentation, and may receive research funding from BHR, which is developing 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. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Future Neurology. 2010;5(1):37­46. © 2010 Future Medicine Ltd.


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