Abstract
Traumatic brain injury (TBI) triggers wide-ranging pathology that impacts multiple biochemical and physiological systems, both inside and outside the brain. Functional recovery in patients is impeded by early onset brain edema, acute and chronic inflammation, delayed cell death, and neurovascular disruption. Drug treatments that target these deficits are under active development, but it seems likely that fully effective therapy may require interruption of the multiplicity of TBI-induced pathological processes either by a cocktail of drug treatments or a single pleiotropic drug. The complex and highly interconnected biochemical network embodied by the neurosteroid system offers multiple options for the research and development of pleiotropic drug treatments that may provide benefit for those who have suffered a TBI. This narrative review examines the neurosteroids and their signaling systems and proposes directions for their utility in the next stage of TBI drug research and development.
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Introduction
TBI initiates a variety of pathological processes that often result in long-term damage and dysfunction. Even mild TBI can disrupt neurovascular function, and trigger necrosis, apoptosis, and inflammation within central nervous system (CNS). It is becoming increasingly clear that inflammation extends well beyond the brain to peripheral tissues and organs resulting in a detrimental disease state that persists long after the initial injury event (for review, see [1]). The complex and varied symptoms experienced after a TBI result from a cascade of tightly interacting biochemical pathophysiological mechanisms locked in enduring feedback loops. It is unlikely that highly selective, single-target drugs could effectively disrupt the whole spectrum of pathology, thereby, markedly limiting their potential benefit. Thus, the use of pleiotropic, multi-mechanism operating drugs may provide better therapeutic opportunities.
Neurosteroids (steroids produced within the brain), also known as neuroactive steroids when they reach and act in the brain after being produced in the peripheral glands, derive from cholesterol or steroid hormones through a series of biosynthesizing enzymes expressed in the nervous system of vertebrates (for reviews of the history of neurosteroids, see [2,3,4]). Neurosteroids play a fundamental role throughout development in addition to brain disease and injury [5,6,7,8,9,10,11,12]. In fact, neurosteroid production is upregulated in response to nervous system trauma [13,14,15], an effect thought to be an endogenous pathophysiological response to brain injury. The link between neurosteroids and TBI was found in an early study by [16], which showed that normal estrous cycling female rats exhibited less edema (brain water content) following controlled cortical impact brain injury than males and pseudopregnant females had the greatest degree of protection against brain injury-induced edema, suggesting that progesterone is neuroprotective following TBI. The role of progesterone for treatment of experimental TBI has been demonstrated in many preclinical studies (reviewed by [17,18,19,20]). Extending from the preclinical observations of the protective role of progesterone in TBI, other neurosteroids including allopregnanolone, estrogen, and testosterone have shown activity in models of brain injury [21,22,23,24,25].
It is important to note that multiple neuroactive steroids have been tested clinically in TBI (e.g., pregnenolone and allopregnanolone; see NCT00623506, NCT01336413, and NCT01673828, Clinicaltrials.gov and [26] and some have been approved for use in CNS indications. IV allopregnanolone, also known as brexanolone, is FDA-approved for use in post-partum depression patients, with benefit likely attributed to its positive allosteric modulatory actions on multiple subtypes of gamma-amino-butyric acid (GABA)-A receptors, including those containing delta-subunits (thought to be extrasynaptic; for reviews, see [27, 28]). Recent evidence suggests that allopregnanolone may also be useful for post-concussive symptoms and post-traumatic stress disorder (PTSD) suffered after injury as evidenced by its improvement of injury-related GABAA receptor signaling abnormalities, the abnormal pro-inflammatory cytokine profile, the low levels of cerebrospinal fluid, and circulating allopregnanolone in patients and reducing activity in anxiety-related brain circuitry [29, 30]. Another recently approved positive allosteric modulator of GABAA receptors, ganaxolone, is a neuroactive steroid synthetic analog approved for the treatment of cyclin-dependent kinase-like 5 deficiency disorder (for review, see [31]) that has been shown to improve neuroinflammatory endpoints in a commonly used model of multiple sclerosis [32] and behavior in stress-induced models of PTSD and depression [33]. Taken together, there is robust preclinical and some clinical evidence that treatment with neuroactive steroids can improve some brain pathologies. Because of their anti-inflammatory, neuroprotective, neurotropic, and behavioral effects, neuroactive steroids may have therapeutic utility in the treatment of TBI.
Given the wealth of neuroprotective evidence for progesterone in preclinical models of TBI, progesterone was evaluated in multiple Phase 2 studies in TBI patients (mostly moderate to severe injury), showing some positive signals [34, 35]. However, progesterone did not produce significant therapeutic benefit in two large Phase 3 trials in patients with moderate to severe TBI [36, 37]. Follow-up analyses of these trials reveal that failure could have resulted from trial design issues including progesterone dose and regimen selection, enrollment of a patient majority with severe and heterogenous injury, adequacy of endpoints, issues discussed in a later section of this review [38,39,40,41]. Therefore, it seems probable the hypothesis that progesterone treatment could improve outcomes in TBI patients was not properly tested in the above two Phase 3 studies.
With recent advances in both preclinical and clinical neurosteroid research and approval of products for CNS conditions, neuroactive steroid therapeutics continue to hold promise as TBI treatments. Of particular importance is the pleiotropic pharmacology of neuroactive steroids, positively impacting multiple pathophysiological processes known to be associated with TBI such as systemic and neuroinflammation, cerebrovascular inflammation, edema, apoptosis, axonal damage, oligodendrocyte loss, synaptic loss, and neurodegeneration. This review provides an overview of neuroactive steroid candidate therapies for TBI and their molecular mechanisms, and presents new directions for neuroactive steroid discovery and development.
Neurosteroid Biochemistry and Pharmacology
The nervous system’s ability to produce neurosteroids de novo from cholesterol that is converted into the key precursor steroid, pregnenolone, arose from the discovery that the key regulatory enzyme, a cytochrome P450 variant encoded by the CYP11A1 gene, was expressed in the brain [42]. This cytochrome P450, known as CYP450scc, is responsible for cleaving cholesterol side chains normally expressed in steroidogenic glandular tissue (e.g., adrenal glands under the control of ACTH), within the mitochondria of peripheral nerves as well as central neurons and glia of the cerebellum and other brain regions [43, 44]. Importantly, it was found that pregnenolone-derived neurosteroids remained constant in the brain despite removal of sources of systemically derived steroids, demonstrating the brain as their source (reviewed by [45,46,47]). The expression of the key neurosteroid synthesizing enzymes at different ages and within various brain regions has been characterized [48, 49]. CYP450scc expression was found to be generally constant in the post-natal period and distributed throughout the brain.
Neurosteroids are generated through the action of multiple aromatase, hydrolase, and reductase enzymes in the cholesterol biosynthetic pathway (Fig. 1). Based on their chemical structures and precursors, neurosteroids are classified as follows:
-
(A)
Pregnane neurosteroids, which are mainly progesterone derivatives, such as allopregnanolone, pregnanolone, and allotetrahydrodeoxycorticosterone
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(B)
Androstane neurosteroids, which are derived from testosterone, such as androstanediol, etiocholanone, and estrogens
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(C)
Sulfated neurosteroids, such as dehydroepiandrosterone sulfate and pregnenolone sulfate
The production of endogenous steroids is generally regulated by the hypothalamic-pituitary axis effects on steroidogenic tissues including gonads and adrenal cortex. Due to their lipophilicity, they can easily reach the brain via the circulation, penetrating the blood–brain barrier (BBB). However, certain steroid molecules, like pregnenolone sulfate, can be substrates for influx and efflux transporters to facilitate access to the brain [50].
One striking interpretation derived from the biosynthetic pathway of neurosteroids is the wide variety of endogenous molecules comprising this network and the complex biochemical control mechanisms associated with their production and degradation. Direct signaling roles for “prominent” components are based partly on interactions with specific receptors and their status as “action-at-a-distance” hormones. However, any of these may have critical roles in the pathophysiology of TBI.
Nuclear hormone receptors (NHR) [51, 52] are major molecular targets for a variety of metabolites (i.e., amino acid as well as fatty acid derivatives, porphyrins, and terpenoids) and other neurosteroids including the sterol family of molecules of which neurosteroids such as progesterone, allopregnanolone, pregnanolone, tetrahydrodeoxycorticosterone, and pregnenolone are members. Neurosteroid ligand-NHR interactions are linked to transcriptional control of gene expression and their activity can have long-lasting influence on cellular physiology and metabolism across a wide variety of tissues, including brain and cerebrovasculature. Target receptors for the array of neurosteroids include the group (or subfamily) 3 A-C such as estrogen receptors (NR3A1 and 2), estrogen-related receptors (NR3B1 and 2), glucocorticoid (NR3C1), mineralocorticoid (NR3C2), progesterone (NR3C3, receptors A and B from the same gene), and androgen (NR3C4) receptors [52]. Neurosteroids may also interact with other NHR subfamilies.
Neurosteroids also can interact with membrane bound receptors. For example, progesterone activates receptors in the membrane-associated progesterone receptor family (PGRMC1, PGRMC2, neudesin, and neuferricin), which are all expressed in the CNS and activate JAK/STAT and other intracellular signaling pathways (reviewed by [53, 54]). Short-term effects of neuroactive steroid treatments could also be mediated by their ability to directly modulate the activity of neuronal ion channels. Neurosteroids such as allopregnanolone (brexanolone) and ganaxolone interact with GABAA receptors containing gamma subunits (synaptic GABAA receptors) as well as delta subunits (extrasynaptic GABAA receptors), acting as positive allosteric modulators (reviewed by [31, 55]). Positive allosteric modulation of the delta subunit-containing receptors increases tonic inhibition upon GABA binding. Some neurosteroids also act as N-methyl-D-aspartate (NMDA) receptor modulators (reviewed by [56]). Certain 3α-hydroxysteroids, such as RU5135, exhibit GABAA receptor antagonist properties [57, 58]. Pregnanolone and pregnenolone sulfated neurosteroids modulate NMDA receptors, although in different ways [59,60,61]. While the action of pregnenolone sulfate is subunit dependent, pregnanolone sulfate mainly inhibits tonic-mediated NMDA receptor neurotransmission, which has been associated with neuroprotective effects [62, 63]. Together, this variety of short- and long-term actions offers mechanisms that could address neuronal pathology from multiple biochemical and physiological modalities.
Progesterone and Progesterone Receptors in TBI
There is a large body of evidence on neuroprotective and pleiotropic actions of progesterone through its receptors (intracellular progesterone receptor and PGRMC1) in TBI (reviewed by [20, 64, 65]). Of interest is the dynamic nature of progesterone levels in the brain [66] as well as the expression of receptors in response to brain injury [14, 67, 68]. The critical role of the progesterone receptor in brain injury is highlighted in ischemic stroke where neuroprotection is reduced in neuron-specific progesterone receptor conditional knockouts [69]. Mechanistic effects of progesterone treatment on neuroprotection and reduction of inflammation after TBI have been reviewed [70,71,72]; however, the precise and relative role of the various progesterone receptor isoforms in neuroprotection has yet to be elucidated [71]. In addition to intracellular progesterone receptor-mediated effects on transcription, other pathways including the Nrf2/ARE, Src-Erk1/2 cascade, and Akt pathways as well as miRNAs may be involved in progesterone-mediated neuroprotection [64, 73,74,75], potentially affecting neural progenitor cell cycling [76]. It is important to note that levels of circulating progesterone following TBI may be quite high [38]. Thus, the use of neurosteroids that may produce optimal progesterone receptor stimulation under injury conditions (i.e., a partial progesterone receptor agonist) may be needed to avoid receptor over-activation.
Additional pharmacologic complexity is conferred by interactions with multiple additional receptors. Progesterone interacts with high affinity on multiple other NHR subtypes (e.g., different progesterone favoring NHRs and glucocorticoid receptors), and it appears to activate membrane receptors having different structural and functional features [53]. Similar receptor promiscuity exists for estrogen and testosterone. Some neurosteroids including allopregnanolone and pregnanolone have potent, direct modulatory activity on ion channel neurotransmitter receptors including GABAA and NMDA receptors. This wide variety of biologically relevant interactions across the landscape of endogenous neurosteroid molecules suggests that there are likely additional neurosteroid receptor and ion channel interactions that have not been discovered. In any case, the neurosteroid class of molecules is broad-spectrum modulators of brain function that offer multiple options for development and testing of pleiotropic TBI treatments.
At least partly due to the multiplicity of receptor interactions, progesterone is considered an archetype of pleiotropic neurosteroid molecules. Multiple studies revealed transcriptional effects of classical nuclear progesterone receptors A and B, as well as putative membrane progesterone receptors including seven transmembrane domain (7TMPRβ) and membrane-associated 25-Dx receptors [65]. Progesterone and allopregnanolone were shown to bind to membrane progesterone receptors in mammalian cells acting as agonists, thus activating stimulatory G-protein-coupled receptors and decreasing apoptosis and necrosis by activation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) and Akt pathways [77]. The direction of the progesterone receptor-mediated actions is routinely supportive of the neuroprotective effect of progesterone that involves reducing BBB dysfunction, amelioration of neuroinflammation, and improvement in myelination [65, 78, 79]
Widely-reproduced preclinical efficacy results in rat and mouse TBI models [18, 80,81,82,83,84,85,86] led to the evaluation of progesterone as a treatment for TBI in multiple Phase 2 and Phase 3 clinical trials [34,35,36,37]. Whereas two initial Phase 2 studies [34, 35] showed promising results with progesterone treatment, subsequent, larger Phase 3 studies [36, 37] failed to show benefit over placebo treatment. One interpretation of these results is that progesterone treatment is simply ineffective in human patients suffering a severe TBI, especially regarding death or vegetative state [87]. However, post-trial analyses [38, 39, 41] suggest there were multiple issues outside of progesterone’s efficacy that contributed to the negative outcome. Among the most notable reasons was the selection of severe TBI patients for the trial. These patients typically suffer multiple non-CNS injuries and are given a wide range of drug treatments to treat these injuries. This clearly could have impeded the ability to observe a treatment effect of progesterone. Furthermore, the choice of progesterone dose level and regimen was not based on careful tests of target engagement in humans, and therefore had a high probability of being inappropriate. Progesterone exhibits an inverted U-shaped dose–response relationship [88] in preclinical studies, and using the wrong dose level in the trial could certainly have resulted in the observed outcomes even though a proper dose of progesterone could have been effective. Based on these and other considerations thoroughly discussed by [38, 39, 41], the SYNAPSE and PROTECT trials likely did not fully test the hypothesis that progesterone treatment is beneficial for TBI patients.
Estrogen and Estrogen Receptors in TBI
Sex-related responses to TBI have been the subject of both preclinical and clinical investigation [84, 89]. While estrogen production by peripheral organs is widely known, the role of estrogen as a neurosteroid is highlighted by its production by astrocytes [90]. Female mice subjected to TBI have improved survival and sensorimotor function compared to males and ovariectomized females [91]. Systemic administration of estrogens has also been shown to reduce neurological deficits in male mice following TBI [92], potentially through inhibiting activation of microglia and astrocytic inflammatory responses with reduced expression of inflammatory and pro-apoptotic genes [92].
It is well known that estrogen serves a neuroprotective role, likely due to reduced neuroinflammation as evidenced by estrogens reducing clinical scores in models of experimental autoimmune encephalomyelitis [93,94,95]. Estrogen-mediated neuroprotection also involves antiapoptotic activity through inhibition of excitotoxicity [96,97,98]. There is substantial evidence for estrogen-induced neuroprotection in a variety of neurodegenerative disease models including Alzheimer’s disease (see reviews by [99, 100]), Parkinson’s disease (see reviews by [101, 102]), and in stroke (see reviews by [103,104,105,106]). Of note, estrogen efficacy is lost in reproductively senescent female mice, potentially due to a loss of expression of both nuclear hormone estrogen receptor subtypes, ERα and ERβ. Estrogen-mediated neuroprotection has also been shown to involve activation of the membrane bound G protein-coupled estrogen receptor, GPR30 in experimental stroke [107]. Taken together, neuroactive steroids with estrogen receptor agonist activity at ERα, ERβ, and/or GPR30 may provide therapeutic benefit in the context of TBI. However, estrogen responsiveness may be reduced with age [108].
Androgens and Androgen Receptors in TBI
The functional effects of modulating androgen receptors (AR) in TBI are poorly understood clinically, are less clearly associated with neuroprotection, and depend on the system under study [109]. It is well known that males have high risk for cerebrovascular disease/stroke [110], suggesting some interaction of androgens to neurovascular function. Whereas male rodents subjected to ischemic stroke or neonatal ischemia tend to have greater brain damage than age-matched females [111], a potential neuroprotective role of estrogen or other neurosteroids in neuroprotection cannot be ruled out. The direct role of androgens in the injured CNS has received limited attention. Pointing to the direct role of testosterone on neurotoxicity, Yang and coworkers found that supplementation of testosterone in castrated male rats led to increased lesion size following ischemic stroke compared to testosterone-depleted males [112]. Their work also showed that testosterone enhanced glutamate excitotoxicity in cultured HT22 cells. While this evidence points to an adverse role for androgen signaling in brain injury (i.e., stroke), clinical findings suggest that testosterone decline associated with aging might have an adverse effect on cognition and can be associated with depression and anxiety; similar mood-related observations have been confirmed in patients taking finasteride [113].
In TBI patients, Renner et al. [114] found no association between sex and outcomes while Styrke and coworkers [115] identified greater disability in women vs. men. In mice subjected to TBI, neuroinflammatory changes, astrogliosis, cell death, and lesion size were greater in males than females [116]. However, Chen and coworkers [117] found that AR knockout mice display increased astrogliosis and necrosis as well as relatively worse neurological deficits than their AR-competent counterparts. Adding to the confusion of whether AR signaling is involved in post-TBI recovery, the expression of ARs decreases with blast-injury in the hippocampus [118] and varies between male and female mice at 3 days post-TBI with males having reduced and females having increased AR expression post-injury [119]. These authors advocate for the relative expression of estrogen to AR levels as being the primary driver, switching to greater estrogen receptor signaling during recovery. While some studies suggest that withdrawal from androgen treatment reduces neurologic damage after insults caused by ischemic stroke, other studies indicate that the effects of testosterone on AR signaling is dose-dependent and can vary from promoting damage to neuroprotective effects [24, 119,120,121,122].
In addition to androgen-mediated effects on the neuropil, testosterone was shown to induce endothelium-dependent vasoconstriction of middle cerebral arteries [123], which could be, in part, mediated by ARs present in endothelial cells. Such vasoconstriction can exacerbate neurovascular reactions to injury. These mixed findings can be attributed to the fact that binding to cytosolic and/or membrane-bound ARs triggers a variety of signaling pathways, some of which might propagate neurotoxicity (e.g., intracellular Ca+2 influx, induction of pro-apoptotic genes and oxidative stress, and compromised mitochondrial function), while some are responsible for neuroprotection (e.g., activation of MAPK/ERK pathway, anti-inflammatory pathways) [24, 122, 124,125,126]. Thus, the relative role of androgen signaling in pathology and potential therapeutic benefits of androgen-related therapeutics (agonists or antagonists) after brain injury is unclear are indeed complex.
Mineralocorticoids and Mineralocorticoid Receptors in TBI
The mineralocorticoid receptor (MR) is a NHR that is activated by both glucocorticoids and the mineralocorticoid, aldosterone. Under physiological conditions, brain glucocorticoids are in high abundance relative to aldosterone and act on MRs [127], often occupying the receptor under physiologic conditions where glucocorticoid concentrations greatly exceed circulating aldosterone levels [128, 129]. In addition to their adverse metabolic effect profile when used chronically, there is considerable evidence that glucocorticoid use in severe TBI patients offers no improvement [130]. Interestingly, GR activation can aggravate brain injury in a variety of conditions [131,132,133] and GR antagonism rescues neuronal loss in the hippocampus post-TBI [134]. The endogenous ligand, aldosterone, is only marginally brain penetrant due to P-glycoprotein efflux [135]; however, certain areas of weak BBB function allow for aldosterone to penetrate and exert actions related to blood pressure and blood volume control where 11-beta-dehydrogenase 2 (HSD2) is expressed to limit glucocorticoid levels at the MR, thereby improving aldosterone activity [136]. MR are distributed throughout the brain, with higher concentrations found in the limbic-frontocortical neurons, hippocampus, hypothalamus, cerebellum, and brain stem motor nuclei, with the nucleus solitarius likely most sensitive to circulating levels of aldosterone given their co-expression of HSD2 [136]. It is likely that MR activity in other brain regions outside of areas with a weak BBB is likely a function of glucocorticoid occupancy of the MR receptor and could contribute to neurotoxic effects of glucocorticoids, particularly under conditions of high stress [137].
The use of available MR antagonists has shed some light on the potential role of modulating MR activity in TBI. One obvious role of the MR in TBI pathology is the regulation of fluid balance and possible effects on edema that is often associated with injury. It is well known that MRs directly modulate the expression of the Na–K ATPase and subsequently the epithelial sodium channel to control hydrostatic balance in kidney and other tissues [138]. Whereas blockade of MRs is expected to reduce fluid retention systemically, MR antagonism does not appear to be effective in managing cerebral edema per se. There is evidence that MR antagonism may be helpful to reduce inflammation in endothelial cells [139]. Numerous studies indicate that modulating cerebrovascular MR activity could be beneficial in managing neurovascular function following brain injury [140,141,142,143,144,145,146,147]. Given the effects of MR antagonism on neurovascular inflammation, combined MR antagonist use with progesterone receptor (PR) agonism could be additive or synergistic at reducing cerebral edema and normalizing neurovascular function in TBI.
MR blockade by synthetic steroid MR antagonists may be anti-inflammatory within the nervous system. In addition to effects on edema, MR antagonism in the brain following TBI has been shown to have anti-inflammatory effects. MR stimulation is pro-inflammatory in non-brain tissues [148, 149]. NF-κB translocation and pro-inflammatory cytokine production was increased by aldosterone in BV-2 microglial cells, effects blocked by spironolactone [150]. In stroke-prone spontaneously hypertensive rats supplemented with NaCl/stroke prone diet for 19 weeks, MR antagonism with eplerenone improved survival and cerebral injury in ischemic and hemorrhagic strokes [151]. In a model of postoperative cognitive impairment, MR expression was activated in the hippocampus CA1 along with expression of inflammatory cytokines, all paralleling cognitive impairment. In this study, MR antagonism improved cognitive dysfunction and reduced hippocampal MR overexpression as well as inflammatory cytokine levels. In a model of dorsal root ganglia inflammation, eplerenone potentiated glucocorticoid anti-inflammatory activity, reduced glial fibrillary acidic protein (GFAP) levels, and improved behavioral nociceptive responses in rats [152]. While MR agonism plays a role in normal brain physiology, the above evidence suggests that synthetic steroids possessing MR antagonist activity could be therapeutically beneficial in TBI.
Role of Liver X Receptor and Retinoid X Receptor in TBI
The potential roles of other NHRs in TBI are still being elucidated. The liver X receptor (LXR) has a role in brain function where its activation modulates inflammation and lipid metabolism. Genetically modified mice lacking one subtype of LXR show a variety of brain-related pathologies, indicating it plays a critical role in brain cell health and survival [153]. A sterol-based agonist of LXR has shown beneficial effects in a mouse model of TBI [154]. A different LXR agonist also improved learning and memory and prevented axonal degeneration in mice following repetitive mild TBI [155]. Genetically modified mice lacking LXR did not improve with LXR agonist treatment, confirming the role of LXR in the effect of drug treatment.
TBI has been associated with disruption of lipid metabolizing enzymes [156] resulting in altered levels of cholesterol end-products and inflammatory mediators [157]. Therefore, LXR activation may provide both anti-inflammatory action and stabilization of lipid metabolism. Since cholesterol represents the upstream precursor of neuroactive steroids, including progesterone, the effects of LXR agonists on neurosteroidogenesis may be worth further investigation.
Additional new treatments for TBI may arise from modulation of the retinoid X receptor (RXR) retinoid-responsive system. RXR is activated by retinoic acid but is distinct from the classic retinoic acid/vitamin A receptor, RAR. Bexarotene is a 3rd generation retinoid compound that is a selective agonist of RXR without effect on RAR. It is in clinical use as an anti-tumor agent. A series of studies have reported bexarotene treatments facilitated axon sprouting and cognitive performance in mouse TBI models that have been mechanistically ascribed to facilitation of BDNF signaling [158], inhibition of apoptosis [159], and via modulation of PPAR\(\gamma\) signaling [160]. Due to RXR’s wide-ranging control of a variety of inflammatory and cell survival pathway, it seems likely that each of these mechanisms contributes to the efficacy of bexarotene and potentially other RXR agonists that are under active development.
Therapeutic Exposure to Neuroactive Steroid-Based Drugs
An often overlooked consideration in research on neuroactive steroid treatments for TBI is the concentration of endogenous neurosteroids at relevant receptors and their relative affinities, and its relation to efficacy. Typical plasma and brain concentrations of most types of endogenous neurosteroids are well below 1 ng/mL [69]. Although we expect neurosteroid concentrations to fluctuate in the receptor local environment as signaling waxes and wanes, endogenous concentrations are 100–1000-fold lower than the peak concentrations of progesterone (for example) expected to occur after an 8 mg/kg level dose of progesterone often used in neuroprotection studies. Variations in circulating and brain progesterone and other hormones after TBI should also be considered when developing neuroactive steroid therapeutics [66, 161]. Furthermore, MRs are modulated by glucocorticoids whose physiologic concentrations are much greater than aldosterone in most brain regions [128]. In physiological conditions, the neurosteroid system is clearly tuned for responding to subtle concentration change. Indeed, progesterone-based oral contraceptives involve changes of less than 1 nM in plasma concentrations. We can only conclude that the changes in brain and plasma concentrations accompanying neuroprotective dose levels would swamp an otherwise tightly controlled biochemical system.
Mechanistic investigations of neuroactive steroid actions are often interpreted as direct effects on NHRs or related neurosteroid receptors, but it is much more likely that biochemical outcomes are the result of widespread disruption of a finely tuned homeostatic system. While this view generally supports the conclusion of neuroactive steroid pleiotropism after therapeutic dose levels, it also means that our current understanding of mechanisms could be quite inaccurate and incomplete, including effects on endocrine and peripheral inflammatory mechanisms induced by TBI that help perpetuate neuroinflammation chronically [162,163,164,165,166]. It is important to evaluate not only whether acute neuroactive steroid use could improve long-term patient outcomes, but also to examine whether patients with chronic post-TBI deficits could benefit with chronic neuroactive steroid therapy.
New Directions
The pharmacology of neuroactive steroids and the wide variety of mechanisms modulated by them provide a wealth of opportunity to generate new, improved treatment strategies for both acute and chronic TBI. Potential breakthroughs could arise from repurposing of available neuroactive steroid molecules to discovery and development of structural analogs having novel physicochemical and pharmacological properties (i.e., enhanced solubility, relative impact on various NHRs, enhanced potency, reduced off-target effects). Based on the foundation of preclinical efficacy, partially promising clinical results and the ability to address known translational pitfalls, improving on progesterone represents a well-founded strategy. For example, the collaboration between the Stein laboratory and the Emory Institute of Drug Discovery has developed multiple water-soluble analogs of progesterone that could address drug dosing and delivery issues associated with the use of progesterone itself [85, 167]. Analogs with different relative affinities for various NHR types or others that favor activation of different signaling pathways may generate better highly pleiotropic neuroprotective or neuro-restorative actions. Finally, the potential for an inverted U-shaped dose–response [38] represents a drawback of progesterone that may be addressed by progesterone analogs that have partial agonist actions and interact with other NHRs that impact TBI pathologies.
Due to the highly interconnected biochemical network that generates multiple active neurosteroids, many having some neuroprotective or neurorestorative effects, drug interventions that change the activity of metabolizing enzymes or otherwise alter the balance of enzyme substrates may offer a different approach for exploiting neuroactive steroids for TBI treatment purposes. For example, it seems likely that inhibition of the 5-\(\alpha\)-reductase that metabolizes progesterone to dihydroprogesterone results in a build-up of progesterone that itself could provide neuroprotection. Considering the concentration issues described above, the pharmacologic levels of progesterone resulting from an externally applied dose could also increase the levels of neurosteroids downstream from progesterone in the biochemical pathway including the GABAA receptor modulator, allopregnanolone. This widespread change in neurosteroid levels would not only alter the activity of metabolizing enzymes but may also trigger compensatory changes in the levels of receptors, metabolizing enzymes, and downstream effectors. Based on our current, limited understanding of this complex system, it is possible that pleiotropic neuroactive steroids that affect multiple NHRs may lead to improved therapeutics for TBI.
Conclusions
As drug discovery and development science embraces pleiotropic approaches for achieving neuroprotection and neurorestoration, pharmacologic modulation of the neurosteroid system represents a fertile area for continued research. Neuroactive steroids are intimately involved in regulation of inflammation, cell health, fluid balance, and growth factors, all mechanisms known to be negatively impacted by TBI. Moreover, the complex interplay of neuroactive steroid synthesis and receptor modulation suggests that we still only have a surface-level understanding of optimal ways to modulate this system for maximum therapeutic benefit.
References
Herrero Babiloni A, Baril AA, Charlebois-Plante C, Jodoin M, Sanchez E, De Baets L, et al. The putative role of neuroinflammation in the interaction between traumatic brain injuries, sleep, pain and other neuropsychiatric outcomes: a state-of-the-art review. J Clin Med. 2023;12:1793.
Baulieu EE, Robel P, Schumacher M. Neurosteroids: beginning of the story. Int Rev Neurobiol. 2001;46:1–32.
Melcangi RC, Giatti S, Garcia-Segura LM. Levels and actions of neuroactive steroids in the nervous system under physiological and pathological conditions: sex-specific features. Neurosci Biobehav Rev. 2016;67:25–40.
Reddy DS. Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res. 2010;186:113–37.
Cameron JL. Interrelationships between hormones, behavior, and affect during adolescence: understanding hormonal, physical, and brain changes occurring in association with pubertal activation of the reproductive axis. Introduction to part III. Ann N Y Acad Sci. 2004;1021:110–23.
Chen S, Wang JM, Irwin RW, Yao J, Liu L, Brinton RD. Allopregnanolone promotes regeneration and reduces β-amyloid burden in a preclinical model of Alzheimer’s disease. PLoS ONE. 2011;6:e24293.
Dang J, Mitkari B, Kipp M, Beyer C. Gonadal steroids prevent cell damage and stimulate behavioral recovery after transient middle cerebral artery occlusion in male and female rats. Brain Behav Immun. 2011;25:715–26.
Fancy SP, Chan JR, Baranzini SE, Franklin RJ, Rowitch DH. Myelin regeneration: a recapitulation of development? Annu Rev Neurosci. 2011;34:21–43.
Liu A, Margaill I, Zhang S, Labombarda F, Coqueran B, Delespierre B, et al. Progesterone receptors: a key for neuroprotection in experimental stroke. Endocrinology. 2012;153:3747–57.
Labombarda F, Pianos A, Liere P, Eychenne B, Gonzalez S, Cambourg A, et al. Injury elicited increase in spinal cord neurosteroid content analyzed by gas chromatography mass spectrometry. Endocrinology. 2006;147:1847–59.
Labombarda F, González S, Lima A, Roig P, Guennoun R, Schumacher M, et al. Progesterone attenuates astro- and microgliosis and enhances oligodendrocyte differentiation following spinal cord injury. Exp Neurol. 2011;231:135–46.
Peper JS, van den Heuvel MP, Mandl RC, Hulshoff Pol HE, van Honk J. Sex steroids and connectivity in the human brain: a review of neuroimaging studies. Psychoneuroendocrinology. 2011;36:1101–13.
De Nicola AF, Labombarda F, Gonzalez Deniselle MC, Gonzalez SL, Garay L, Meyer M, et al. Progesterone neuroprotection in traumatic CNS injury and motoneuron degeneration. Front Neuroendocrinol. 2009;30:173–87.
Meffre D, Labombarda F, Delespierre B, Chastre A, De Nicola AF, Stein DG, et al. Distribution of membrane progesterone receptor alpha in the male mouse and rat brain and its regulation after traumatic brain injury. Neuroscience. 2013;231:111–24.
Wagner AK, McCullough EH, Niyonkuru C, Ozawa H, Loucks TL, Dobos JA, et al. Acute serum hormone levels: characterization and prognosis after severe traumatic brain injury. J Neurotrauma. 2011;28:871–88.
Roof RL, Duvdevani R, Stein DG. Gender influences outcome of brain injury: progesterone plays a protective role. Brain Res. 1993;607:333–6.
Schumacher M, Mattern C, Ghoumari A, Oudinet JP, Liere P, Labombarda F, et al. Revisiting the roles of progesterone and allopregnanolone in the nervous system: resurgence of the progesterone receptors. Prog Neurobiol. 2014;113:6–39.
He J, Evans CO, Hoffman SW, Oyesiku NM, Stein DG. Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury. Exp Neurol. 2004;189:404–12.
He J, Hoffman SW, Stein DG. Allopregnanolone, a progesterone metabolite, enhances behavioral recovery and decreases neuronal loss after traumatic brain injury. Restor Neurol Neurosci. 2004;22:19–31.
Guennoun R. Progesterone in the brain: hormone, neurosteroid and neuroprotectant. Int J Mol Sci. 2020;21:5271.
Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma. 2005;22:106–18.
Djebaili M, Hoffman SW, Stein DG. Allopregnanolone and progesterone decrease cell death and cognitive deficits after a contusion of the rat pre-frontal cortex. Neuroscience. 2004;123:349–59.
Labombarda F, Ghoumari AM, Liere P, De Nicola AF, Schumacher M, Guennoun R. Neuroprotection by steroids after neurotrauma in organotypic spinal cord cultures: a key role for progesterone receptors and steroidal modulators of GABA(A) receptors. Neuropharmacology. 2013;71:46–55.
Uchida M, Palmateer JM, Herson PS, DeVries AC, Cheng J, Hurn PD. Dose-dependent effects of androgens on outcome after focal cerebral ischemia in adult male mice. J Cereb Blood Flow Metab. 2009;29:1454–62.
VanLandingham JW, Cekic M, Cutler SM, Hoffman SW, Washington ER, Johnson SJ, et al. Progesterone and its metabolite allopregnanolone differentially regulate hemostatic proteins after traumatic brain injury. J Cereb Blood Flow Metab. 2008;28:1786–94.
Marx CE, Naylor JC, Kilts JD, Dunn CE, Tupler LA, Szabo ST, et al. Frontiers in Neuroscience Neurosteroids and traumatic brain injury: translating biomarkers to therapeutics; overview and pilot investigations in Iraq and Afghanistan era veterans. In: Laskowitz D, Grant G, editors. Translational Research in Traumatic Brain Injury. Boca Raton (FL): CRC Press/Taylor and Francis Group© 2016 by Taylor & Francis Group, LLC.; 2016. Chapter 7.
Pinna G. Allopregnanolone (1938–2019): a trajectory of 80 years of outstanding scientific achievements. Neurobiol Stress. 2020;13:100246.
Edinoff AN, Odisho AS, Lewis K, Kaskas A, Hunt G, Cornett EM, et al. Brexanolone, a GABA(A) modulator, in the treatment of postpartum depression in adults: a comprehensive review. Front Psychiatry. 2021;12:699740.
Kinzel P, Marx CE, Sollmann N, Hartl E, Guenette JP, Kaufmann D, et al. Serum neurosteroid levels are associated with cortical thickness in individuals diagnosed with posttraumatic stress disorder and history of mild traumatic brain injury. Clin EEG Neurosci. 2020;51:285–99.
Rasmusson AM, Marx CE, Pineles SL, Locci A, Scioli-Salter ER, Nillni YI, et al. Neuroactive steroids and PTSD treatment. Neurosci Lett. 2017;649:156–63.
Lamb YN. Ganaxolone: First Approval. Drugs. 2022;82:933–40.
Paul AM, Branton WG, Walsh JG, Polyak MJ, Lu JQ, Baker GB, et al. GABA transport and neuroinflammation are coupled in multiple sclerosis: regulation of the GABA transporter-2 by ganaxolone. Neuroscience. 2014;273:24–38.
Pinna G, Rasmusson AM. Ganaxolone improves behavioral deficits in a mouse model of post-traumatic stress disorder. Front Cell Neurosci. 2014;8:256.
Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, et al. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med. 2007;49(391–402):e1-2.
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. 2008;12:R61.
Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, et al. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med. 2014;371:2457–66.
Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, MacAllister T, Ward JD, et al. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med. 2014;371:2467–76.
Stein DG. Embracing failure: what the Phase III progesterone studies can teach about TBI clinical trials. Brain Inj. 2015;29:1259–72.
Schumacher M, Denier C, Oudinet JP, Adams D, Guennoun R. Progesterone neuroprotection: The background of clinical trial failure. J Steroid Biochem Mol Biol. 2016;160:53–66.
Maas AI, Menon DK, Lingsma HF, Pineda JA, Sandel ME, Manley GT. Re-orientation of clinical research in traumatic brain injury: report of an international workshop on comparative effectiveness research. J Neurotrauma. 2012;29:32–46.
Menon DK, Maas AI, Traumatic brain injury in,. Progress, failures and new approaches for TBI research. Nat Rev Neurol. 2014;2015(11):71–2.
Omura T, Sato R, Cooper DY, Rosenthal O, Estabrook RW. Function of cytochrome P-450 of microsomes. Fed Proc. 1965;24:1181–9.
Goascogne C, Gouézou M, Robel P, Defaye G, Chambaz E, Waterman MR, et al. The cholesterol side-chain cleavage complex in human brain white matter. J Neuroendocrinol. 1989;1:153–6.
Le Goascogne C, Robel P, Gouézou M, Sananès N, Baulieu EE, Waterman M. Neurosteroids: cytochrome P-450scc in rat brain. Science. 1987;237:1212–5.
Robel P, Baulieu EE. Neuro-steroids: 3?-hydroxy-?(5)-derivatives in the rodent brain. Neurochem Int. 1985;7:953–8.
Tsutsui K, Ukena K, Takase M, Kohchi C, Lea RW. Neurosteroid biosynthesis in vertebrate brains. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1999;124:121–9.
Paul SM, Pinna G, Guidotti A. Allopregnanolone: from molecular pathophysiology to therapeutics. A historical perspective. Neurobiol Stress. 2020;12:100215.
Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, et al. Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc Natl Acad Sci U S A. 2006;103:14602–7.
Kohchi C, Ukena K, Tsutsui K. Age- and region-specific expressions of the messenger RNAs encoding for steroidogenic enzymes p450scc, P450c17 and 3beta-HSD in the postnatal rat brain. Brain Res. 1998;801:233–8.
Schäfer AM, Meyer Zu Schwabedissen HE, Grube M. Expression and function of organic anion transporting polypeptides in the human brain: physiological and pharmacological implications. Pharmaceutics. 2021;13:834.
Tao LJ, Seo DE, Jackson B, Ivanova NB, Santori FR. Nuclear hormone receptors and their ligands: metabolites in control of transcription. Cells. 2020;2606.
A unified nomenclature system for the nuclear receptor superfamily. Cell. 1999;97:161–3.
Guennoun R, Meffre D, Labombarda F, Gonzalez SL, Gonzalez Deniselle MC, Stein DG, et al. The membrane-associated progesterone-binding protein 25-Dx: expression, cellular localization and up-regulation after brain and spinal cord injuries. Brain Res Rev. 2008;57:493–505.
Wendler A, Wehling M. Many or too many progesterone membrane receptors? Clinical implications. Trends Endocrinol Metab. 2022;33:850–68.
Gunn BG, Cunningham L, Mitchell SG, Swinny JD, Lambert JJ, Belelli D. GABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response. Front Neuroendocrinol. 2015;36:28–48.
Alqurashi H, Ortega Asencio I, Lambert DW. The emerging potential of extracellular vesicles in cell-free tissue engineering and regenerative medicine. Tissue Eng Part B Rev. 2021;27:530–538.
Hunt P, Clements-Jewery S. A steroid derivative, R 5135, antagonizes the GABA/benzodiazepine receptor interaction. Neuropharmacology. 1981;20:357–61.
Simmonds MA, Turner JP. Antagonism of inhibitory amino acids by the steroid derivative RU5135. Br J Pharmacol. 1985;84:631–5.
Adamusová E, Cais O, Vyklický V, Kudová E, Chodounská H, Horák M, et al. Pregnenolone sulfate activates NMDA receptor channels. Physiol Res. 2013;62:731–6.
Elfverson M, Linde AM, Le Grevès P, Zhou Q, Nyberg F, Johansson T. Neurosteroids allosterically modulate the ion pore of the NMDA receptor consisting of NR1/NR2B but not NR1/NR2A. Biochem Biophys Res Commun. 2008;372:305–8.
Korinek M, Kapras V, Vyklicky V, Adamusova E, Borovska J, Vales K, et al. Neurosteroid modulation of N-methyl-D-aspartate receptors: molecular mechanism and behavioral effects. Steroids. 2011;76:1409–18.
Kudova E, Chodounska H, Slavikova B, Budesinsky M, Nekardova M, Vyklicky V, et al. A new class of potent N-methyl-D-aspartate receptor inhibitors: sulfated neuroactive steroids with lipophilic D-ring modifications. J Med Chem. 2015;58:5950–66.
Vyklicky V, Smejkalova T, Krausova B, Balik A, Korinek M, Borovska J, et al. Preferential inhibition of tonically over phasically activated NMDA receptors by pregnane derivatives. J Neurosci. 2016;36:2161–75.
Zhang M, Wu J, Ding H, Wu W, Xiao G. Progesterone provides the pleiotropic neuroprotective effect on traumatic brain injury through the Nrf2/ARE signaling pathway. Neurocrit Care. 2017;26:292–300.
Brinton RD, Thompson RF, Foy MR, Baudry M, Wang J, Finch CE, et al. Progesterone receptors: form and function in brain. Front Neuroendocrinol. 2008;29:313–39.
Meffre D, Pianos A, Liere P, Eychenne B, Cambourg A, Schumacher M, et al. Steroid profiling in brain and plasma of male and pseudopregnant female rats after traumatic brain injury: analysis by gas chromatography/mass spectrometry. Endocrinology. 2007;148:2505–17.
Meffre D, Delespierre B, Gouézou M, Leclerc P, Vinson GP, Schumacher M, et al. The membrane-associated progesterone-binding protein 25-Dx is expressed in brain regions involved in water homeostasis and is up-regulated after traumatic brain injury. J Neurochem. 2005;93:1314–26.
Allen RS, Sayeed I, Oumarbaeva Y, Morrison KC, Choi PH, Pardue MT, et al. Progesterone treatment shows greater protection in brain vs. retina in a rat modelof middle cerebral artery occlusion: progesterone receptor levels may play an important role. Restor Neurol Neurosci. 2016;34:947–63.
Zhu X, Frechou M, Liere P, Zhang S, Pianos A, Fernandez N, et al. A role of endogenous progesterone in stroke cerebroprotection revealed by the neural-specific deletion of its intracellular receptors. J Neurosci. 2017;37:10998–1020.
Cooke PS, Nanjappa MK, Yang Z, Wang KK. Therapeutic effects of progesterone and its metabolites in traumatic brain injury may involve non-classical signaling mechanisms. Front Neurosci. 2013;7:108.
Schumacher M, Guennoun R, Stein DG, De Nicola AF. Progesterone: therapeutic opportunities for neuroprotection and myelin repair. Pharmacol Ther. 2007;116:77–106.
Sayeed I, Stein DG. Progesterone as a neuroprotective factor in traumatic and ischemic brain injury. Prog Brain Res. 2009;175:219–37.
Cai W, Zhu Y, Furuya K, Li Z, Sokabe M, Chen L. Two different molecular mechanisms underlying progesterone neuroprotection against ischemic brain damage. Neuropharmacology. 2008;55:127–38.
Ishrat T, Sayeed I, Atif F, Hua F, Stein DG. Progesterone is neuroprotective against ischemic brain injury through its effects on the phosphoinositide 3-kinase/protein kinase B signaling pathway. Neuroscience. 2012;210:442–50.
Cochrane DR, Spoelstra NS, Richer JK. The role of miRNAs in progesterone action. Mol Cell Endocrinol. 2012;357:50–9.
Liu L, Wang J, Zhao L, Nilsen J, McClure K, Wong K, et al. Progesterone increases rat neural progenitor cell cycle gene expression and proliferation via extracellularly regulated kinase and progesterone receptor membrane components 1 and 2. Endocrinology. 2009;150:3186–96.
Pang Y, Dong J, Thomas P. Characterization, neurosteroid binding and brain distribution of human membrane progesterone receptors δ and epsilon (mPRδ and mPR{epsilon}) and mPRδ involvement in neurosteroid inhibition of apoptosis. Endocrinology. 2013;154:283–95.
Chen G, Shi J, Jin W, Wang L, Xie W, Sun J, et al. Progesterone administration modulates TLRs/NF-kappaB signaling pathway in rat brain after cortical contusion. Ann Clin Lab Sci. 2008;38:65–74.
Si D, Li J, Liu J, Wang X, Wei Z, Tian Q, et al. Progesterone protects blood-brain barrier function and improves neurological outcome following traumatic brain injury in rats. Exp Ther Med. 2014;8:1010–4.
Stein DG. Progesterone exerts neuroprotective effects after brain injury. Brain Res Rev. 2008;57:386–97.
Cutler SM, Cekic M, Miller DM, Wali B, VanLandingham JW, Stein DG. Progesterone improves acute recovery after traumatic brain injury in the aged rat. J Neurotrauma. 2007;24:1475–86.
Hua F, Wang J, Ishrat T, Wei W, Atif F, Sayeed I, et al. Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone. J Neuroinflammation. 2011;8:42.
Guo Q, Sayeed I, Baronne LM, Hoffman SW, Guennoun R, Stein DG. Progesterone administration modulates AQP4 expression and edema after traumatic brain injury in male rats. Exp Neurol. 2006;198:469–78.
Späni CB, Braun DJ, Van Eldik LJ. Sex-related responses after traumatic brain injury: considerations for preclinical modeling. Front Neuroendocrinol. 2018;50:52–66.
Wali B, Sayeed I, Guthrie DB, Natchus MG, Turan N, Liotta DC, et al. Evaluating the neurotherapeutic potential of a water-soluble progesterone analog after traumatic brain injury in rats. Neuropharmacology. 2016;109:148–58.
Tang H, Hua F, Wang J, Sayeed I, Wang X, Chen Z, et al. Progesterone and vitamin D: improvement after traumatic brain injury in middle-aged rats. Horm Behav. 2013;64:527–38.
Lin C, He H, Li Z, Liu Y, Chao H, Ji J, et al. Efficacy of progesterone for moderate to severe traumatic brain injury: a meta-analysis of randomized clinical trials. Sci Rep. 2015;5:13442.
Stein, DG. Lost in translation understanding the failure of progesterone/traumatic brain injury Phase III trials. Future Neurol. 2016;11(1):9–13.
Blaya MO, Raval AP, Bramlett HM. Traumatic brain injury in women across lifespan. Neurobiol Dis. 2022;164:105613.
Zwain IH, Yen SS. Neurosteroidogenesis in astrocytes, oligodendrocytes, and neurons of cerebral cortex of rat brain. Endocrinology. 1999;140:3843–52.
Clevenger AC, Kim H, Salcedo E, Yonchek JC, Rodgers KM, Orfila JE, et al. Endogenous sex steroids dampen neuroinflammation and improve outcome of traumatic brain injury in mice. J Mol Neurosci. 2018;64:410–20.
Schaible EV, Windschügl J, Bobkiewicz W, Kaburov Y, Dangel L, Krämer T, et al. 2-Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF-1α response after traumatic brain injury in mice. J Neurochem. 2014;129:940–54.
Garidou L, Laffont S, Douin-Echinard V, Coureau C, Krust A, Chambon P, et al. Estrogen receptor alpha signaling in inflammatory leukocytes is dispensable for 17beta-estradiol-mediated inhibition of experimental autoimmune encephalomyelitis. J Immunol. 2004;173:2435–42.
Ito A, Bebo BF Jr, Matejuk A, Zamora A, Silverman M, Fyfe-Johnson A, et al. Estrogen treatment down-regulates TNF-alpha production and reduces the severity of experimental autoimmune encephalomyelitis in cytokine knockout mice. J Immunol. 2001;167:542–52.
Bebo BF Jr, Fyfe-Johnson A, Adlard K, Beam AG, Vandenbark AA, Offner H. Low-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains. J Immunol. 2001;166:2080–9.
Heron P, Daya S. 17Beta-estradiol attenuates quinolinic acid insult in the rat hippocampus. Metab Brain Dis. 2001;16:187–98.
Weaver CE Jr, Park-Chung M, Gibbs TT, Farb DH. 17beta-Estradiol protects against NMDA-induced excitotoxicity by direct inhibition of NMDA receptors. Brain Res. 1997;761:338–41.
Hilton GD, Nunez JL, Bambrick L, Thompson SM, McCarthy MM. Glutamate-mediated excitotoxicity in neonatal hippocampal neurons is mediated by mGluR-induced release of Ca++ from intracellular stores and is prevented by estradiol. Eur J Neurosci. 2006;24:3008–16.
Radaghdam S, Karamad V, Nourazarian A, Shademan B, Khaki-Khatibi F, Nikanfar M. Molecular mechanisms of sex hormones in the development and progression of Alzheimer’s disease. Neurosci Lett. 2021;764:136221.
Sohrabji F. Estrogen: a neuroprotective or proinflammatory hormone? Emerging evidence from reproductive aging models. Ann N Y Acad Sci. 2005;1052:75–90.
Litim N, Morissette M, Di Paolo T. Neuroactive gonadal drugs for neuroprotection in male and female models of Parkinson’s disease. Neurosci Biobehav Rev. 2016;67:79–88.
Morissette M, Al Sweidi S, Callier S, Di Paolo T. Estrogen and SERM neuroprotection in animal models of Parkinson’s disease. Mol Cell Endocrinol. 2008;290:60–9.
Hurn PD, Brass LM. Estrogen and stroke: a balanced analysis. Stroke. 2003;34:338–41.
Hurn PD, Macrae IM. Estrogen as a neuroprotectant in stroke. J Cereb Blood Flow Metab. 2000;20:631–52.
Garcia-Segura LM, Azcoitia I, DonCarlos LL. Neuroprotection by estradiol. Prog Neurobiol. 2001;63:29–60.
Merchenthaler I, Dellovade TL, Shughrue PJ. Neuroprotection by estrogen in animal models of global and focal ischemia. Ann N Y Acad Sci. 2003;1007:89–100.
Zhang B, Subramanian S, Dziennis S, Jia J, Uchida M, Akiyoshi K, et al. Estradiol and G1 reduce infarct size and improve immunosuppression after experimental stroke. J Immunol. 2010;184:4087–94.
Foster TC. Interaction of rapid signal transduction cascades and gene expression in mediating estrogen effects on memory over the life span. Front Neuroendocrinol. 2005;26:51–64.
Herson PS, Koerner IP, Hurn PD. Sex, sex steroids, and brain injury. Semin Reprod Med. 2009;27:229–39.
Rothwell PM, Coull AJ, Silver LE, Fairhead JF, Giles MF, Lovelock CE, et al. Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study). Lancet. 2005;366:1773–83.
Hill CA, Fitch RH. Sex differences in mechanisms and outcome of neonatal hypoxia-ischemia in rodent models: implications for sex-specific neuroprotection in clinical neonatal practice. Neurol Res Int. 2012;2012:867531.
Yang SH, Perez E, Cutright J, Liu R, He Z, Day AL, et al. Testosterone increases neurotoxicity of glutamate in vitro and ischemia-reperfusion injury in an animal model. J Appl Physiol. 1985;2002(92):195–201.
Frye CA, Lembo VF, Walf AA. Progesterone’s effects on cognitive performance of male mice are independent of progestin receptors but relate to increases in GABAA activity in the hippocampus and cortex. Front Endocrinol (Lausanne). 2020;11:552805.
Renner C, Hummelsheim H, Kopczak A, Steube D, Schneider HJ, Schneider M, et al. The influence of gender on the injury severity, course and outcome of traumatic brain injury. Brain Inj. 2012;26:1360–71.
Styrke J, Sojka P, Björnstig U, Bylund PO, Stålnacke BM. Sex-differences in symptoms, disability, and life satisfaction three years after mild traumatic brain injury: a population-based cohort study. J Rehabil Med. 2013;45:749–57.
Villapol S, Loane DJ, Burns MP. Sexual dimorphism in the inflammatory response to traumatic brain injury. Glia. 2017;65:1423–38.
Chen YH, Chen YC, Hwang LL, Yang LY, Lu DY. Deficiency in androgen receptor aggravates traumatic brain injury-induced pathophysiology and motor deficits in mice. Molecules. 2021;26:6250.
Hoffman JR, Zuckerman A, Ram O, Sadot O, Cohen H. Changes in hippocampal androgen receptor density and behavior in Sprague-Dawley male rats exposed to a low-pressure blast wave. Brain Plast. 2020;5:135–45.
Golz C, Kirchhoff FP, Westerhorstmann J, Schmidt M, Hirnet T, Rune GM, et al. Sex hormones modulate pathogenic processes in experimental traumatic brain injury. J Neurochem. 2019;150:173–87.
Cheng J, Alkayed NJ, Hurn PD. Deleterious effects of dihydrotestosterone on cerebral ischemic injury. J Cereb Blood Flow Metab. 2007;27:1553–62.
Hammond J, Le Q, Goodyer C, Gelfand M, Trifiro M, LeBlanc A. Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons. J Neurochem. 2001;77:1319–26.
Quillinan N, Deng G, Grewal H, Herson PS. Androgens and stroke: good, bad or indifferent? Exp Neurol. 2014;259:10–5.
Gonzales RJ, Krause DN, Duckles SP. Testosterone suppresses endothelium-dependent dilation of rat middle cerebral arteries. Am J Physiol Heart Circ Physiol. 2004;286:H552–60.
Cunningham RL, Giuffrida A, Roberts JL. Androgens induce dopaminergic neurotoxicity via caspase-3-dependent activation of protein kinase Cdelta. Endocrinology. 2009;150:5539–48.
Pomara C, Neri M, Bello S, Fiore C, Riezzo I, Turillazzi E. Neurotoxicity by synthetic androgen steroids: oxidative stress, apoptosis, and neuropathology: a review. Curr Neuropharmacol. 2015;13:132–45.
Yang L, Zhou R, Tong Y, Chen P, Shen Y, Miao S, et al. Neuroprotection by dihydrotestosterone in LPS-induced neuroinflammation. Neurobiol Dis. 2020;140:104814.
Paul SN, Wingenfeld K, Otte C, Meijer OC. Brain mineralocorticoid receptor in health and disease: From molecular signalling to cognitive and emotional function. Br J Pharmacol. 2022;179:3205–19.
Yongue BG, Roy EJ. Endogenous aldosterone and corticosterone in brain cell nuclei of adrenal-intact rats: regional distribution and effects of physiological variations in serum steroids. Brain Res. 1987;436:49–61.
Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol. 1994;105:R11–7.
Segatore M. Corticosteroids and traumatic brain injury: status at the end of the decade of the brain. J Neurosci Nurs. 1999;31:239–50.
Goodman Y, Bruce AJ, Cheng B, Mattson MP. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. J Neurochem. 1996;66:1836–44.
Sapolsky RM, Krey LC, McEwen BS. Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging. J Neurosci. 1985;5:1222–7.
Sapolsky RM, Pulsinelli WA. Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications. Science. 1985;229:1397–400.
McCullers DL, Sullivan PG, Scheff SW, Herman JP. Mifepristone protects CA1 hippocampal neurons following traumatic brain injury in rat. Neuroscience. 2002;109:219–30.
Ueda K, Okamura N, Hirai M, Tanigawara Y, Saeki T, Kioka N, et al. Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J Biol Chem. 1992;267:24248–52.
Geerling JC, Loewy AD. Aldosterone in the brain. Am J Physiol Renal Physiol. 2009;297:F559–76.
Kellner M, Wiedemann K. Mineralocorticoid receptors in brain, in health and disease: possibilities for new pharmacotherapy. Eur J Pharmacol. 2008;583:372–8.
Derfoul A, Robertson NM, Lingrel JB, Hall DJ, Litwack G. Regulation of the human Na/K-ATPase beta1 gene promoter by mineralocorticoid and glucocorticoid receptors. J Biol Chem. 1998;273:20702–11.
Jover E, Matilla L, Garaikoetxea M, Fernández-Celis A, Muntendam P, Jaisser F, et al. Beneficial effects of mineralocorticoid receptor pathway blockade against endothelial inflammation induced by SARS-CoV-2 spike protein. Biomedicines. 2021;9:639.
Chen Y, Yu Y, Qiao J, Zhu L, Xiao Z. Mineralocorticoid receptor excessive activation involved in glucocorticoid-related brain injury. Biomed Pharmacother. 2020;122:109695.
Diaz-Otero JM, Yen TC, Fisher C, Bota D, Jackson WF, Dorrance AM. Mineralocorticoid receptor antagonism improves parenchymal arteriole dilation via a TRPV4-dependent mechanism and prevents cognitive dysfunction in hypertension. Am J Physiol Heart Circ Physiol. 2018;315:H1304–15.
Dinh QN, Young MJ, Evans MA, Drummond GR, Sobey CG, Chrissobolis S. Aldosterone-induced oxidative stress and inflammation in the brain are mediated by the endothelial cell mineralocorticoid receptor. Brain Res. 2016;1637:146–53.
Dorrance AM, Rupp NC, Nogueira EF. Mineralocorticoid receptor activation causes cerebral vessel remodeling and exacerbates the damage caused by cerebral ischemia. Hypertension. 2006;47:590–5.
Gomez-Sanchez EP. Brain mineralocorticoid receptors: orchestrators of hypertension and end-organ disease. Curr Opin Nephrol Hypertens. 2004;13:191–6.
Gomez-Sanchez EP, Gomez-Sanchez CE. Central regulation of blood pressure by the mineralocorticoid receptor. Mol Cell Endocrinol. 2012;350:289–98.
Osmond JM, Rigsby CS, Dorrance AM. Is the mineralocorticoid receptor a potential target for stroke prevention? Clin Sci (Lond). 2008;114:37–47:e12460.
Pires PW, McClain JL, Hayoz SF, Dorrance AM. Mineralocorticoid receptor antagonism prevents obesity-induced cerebral artery remodeling and reduces white matter injury in rats. Microcirculation. 2018;25.
Neves MF, Amiri F, Virdis A, Diep QN, Schiffrin EL. Role of aldosterone in angiotensin II-induced cardiac and aortic inflammation, fibrosis, and hypertrophy. Can J Physiol Pharmacol. 2005;83:999–1006.
Leroy V, De Seigneux S, Agassiz V, Hasler U, Rafestin-Oblin ME, Vinciguerra M, et al. Aldosterone activates NF-kappaB in the collecting duct. J Am Soc Nephrol. 2009;20:131–44.
Chantong B, Kratschmar DV, Nashev LG, Balazs Z, Odermatt A. Mineralocorticoid and glucocorticoid receptors differentially regulate NF-kappaB activity and pro-inflammatory cytokine production in murine BV-2 microglial cells. J Neuroinflammation. 2012;9:260.
Rocha R, Stier CT Jr. Pathophysiological effects of aldosterone in cardiovascular tissues. Trends Endocrinol Metab. 2001;12:308–14.
Ibrahim SIA, Xie W, Strong JA, Tonello R, Berta T, Zhang JM. Mineralocorticoid antagonist improves glucocorticoid receptor signaling and dexamethasone analgesia in an animal model of low back pain. Front Cell Neurosci. 2018;12:453.
Song X, Wu W, Warner M, Gustafsson J. Liver X receptor regulation of glial cell functions in the CNS. Biomedicines. 2022;10:2165.
Yu S, Li S, Henke A, Muse ED, Cheng B, Welzel G, et al. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases. Faseb j. 2016;30:2570–9.
Namjoshi DR, Martin G, Donkin J, Wilkinson A, Stukas S, Fan J, et al. The liver X receptor agonist GW3965 improves recovery from mild repetitive traumatic brain injury in mice partly through apolipoprotein E. PLoS ONE. 2013;8:e53529.
Cartagena CM, Ahmed F, Burns MP, Pajoohesh-Ganji A, Pak DT, Faden AI, et al. Cortical injury increases cholesterol 24S hydroxylase (Cyp46) levels in the rat brain. J Neurotrauma. 2008;25:1087–98.
Cartagena CM, Burns MP, Rebeck GW. 24S-hydroxycholesterol effects on lipid metabolism genes are modeled in traumatic brain injury. Brain Res. 2010;1319:1–12.
He J, Huang Y, Liu H, Sun X, Wu J, Zhang Z, et al. Bexarotene promotes microglia/macrophages-specific brain-derived neurotrophic factor expression and axon sprouting after traumatic brain injury. Exp Neurol. 2020;334:113462.
Liu H, Liu S, Tian X, Wang Q, Rao J, Wang Y, et al. Bexarotene attenuates focal cerebral ischemia-reperfusion injury via the suppression of JNK/caspase-3 signaling pathway. Neurochem Res. 2019;44:2809–20.
He J, Liu H, Zhong J, Guo Z, Wu J, Zhang H, et al. Bexarotene protects against neurotoxicity partially through a PPARγ-dependent mechanism in mice following traumatic brain injury. Neurobiol Dis. 2018;117:114–24.
Zhong YH, Wu HY, He RH, Zheng BE, Fan JZ. Sex differences in sex hormone profiles and prediction of consciousness recovery after severe traumatic brain injury. Front Endocrinol (Lausanne). 2019;10:261.
Caplan HW, Prabhakara KS, Toledano Furman NE, Zorofchian S, Kumar A, Martin C, et al. Combination therapy with Treg and mesenchymal stromal cells enhances potency and attenuation of inflammation after traumatic brain injury compared to monotherapy. Stem Cells. 2021;39:358–70.
Hubbard WB, Dong JF, Cruz MA, Rumbaut RE. Links between thrombosis and inflammation in traumatic brain injury. Thromb Res. 2021;198:62–71.
Milleville KA, Awan N, Disanto D, Kumar RG, Wagner AK. Early chronic systemic inflammation and associations with cognitive performance after moderate to severe TBI. Brain Behav Immun Health. 2021;11:100185.
Powner DJ, Boccalandro C, Alp MS, Vollmer DG. Endocrine failure after traumatic brain injury in adults. Neurocrit Care. 2006;5:61–70.
Ritzel RM, Doran SJ, Barrett JP, Henry RJ, Ma EL, Faden AI, et al. Chronic alterations in systemic immune function after traumatic brain injury. J Neurotrauma. 2018;35:1419–36.
Fritzemeier RG, van der Westhuyzen AE, D’Erasmo M, Sharma SK, Bartsch P, Hodson LE, et al. Neurotherapeutic potential of water-soluble pH-responsive prodrugs of EIDD-036 in traumatic brain injury. J Med Chem. 2023;66:5397–414.
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Verdoorn, T.A., Parry, T.J., Pinna, G. et al. Neurosteroid Receptor Modulators for Treating Traumatic Brain Injury. Neurotherapeutics 20, 1603–1615 (2023). https://doi.org/10.1007/s13311-023-01428-7
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DOI: https://doi.org/10.1007/s13311-023-01428-7