NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012.

Cover of Jasper's Basic Mechanisms of the Epilepsies

Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition.

Show details

Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy

and .

Author Information

Certain steroid hormone metabolites that have activity as modulators of GABAA receptors but lack conventional hormonal effects—including allopregnanolone and allotetrahydrodeoxycorticosterone—are synthesized within the brain, predominantly in principle (excitatory) neurons, and also in peripheral tissues. At low concentrations, such neurosteroids potentiate GABAA receptor currents, whereas at higher concentrations they directly activate the receptor; large magnitude effects occur on nonsynaptic δ subunit-containing GABAA receptors that mediate tonic currents. GABAA receptor modulatory neurosteroids confer seizure protection in diverse animal models, without tolerance during chronic administration. Endogenous neurosteroids may play a role in catamenial epilepsy, stress-induced changes in seizure susceptibility, temporal lobe epilepsy, and alcohol withdrawal seizures. Moreover, neurosteroid replacement with natural or synthetic neurosteroids may be useful in these conditions and more generally in the treatment of partial seizures. Ganaxolone, the synthetic 3β-methyl analog of allopregnanolone, has been evaluated in clinical trials for the treatment of epilepsy. It appears to be an efficacious, well-tolerated and safe treatment for partial seizures. Neurosteroids and analogs such as ganaxolone show promise in the treatment of diverse forms of epilepsy.

INTRODUCTION

The term ‘neurosteroid’ was originally coined in 1981 by the French endocrinologist Étienne-Émile Baulieu to refer to steroids that are synthesized de novo in the nervous system from cholesterol independently of the peripheral steroidogenic endocrine glands.1 Paul and Purdy then characterized ‘neuroactive steroids’ as “natural or synthetic steroids that rapidly alter the excitability of neurons by binding to membrane-bound receptors such as those for inhibitory and (or) excitatory neurotransmitters.”2 This chapter is concerned with the anticonvulsant and antiepileptogenic properties of neurosteroid-related steroid molecules (i.e., related to endogenously synthesized steroids) that meet the Paul and Purdy definition of neuroactive steroids by virtue of their pharmacological actions as positive allosteric modulators of GABAA receptors. The effect of these steroids on GABAA receptors occurs through a direct action on GABAA receptors and is not related to interactions with classical steroid hormone receptors that regulate gene transcription. Indeed, GABAA receptor modulatory neurosteroids are not themselves active at intracellular steroid receptors. We will make scant mention of other endogenous neurosteroids that exert other types of pharmacological actions, such as inhibition of GABAA receptors or effects on excitatory amino acid receptors (pregnenolone sulfate is an example of such a steroid) although it is conceivable that neurosteroids with such actions could play a role in regulating seizure susceptibility.

It has been known since the 1940s from the pioneering work of Hans Selye that naturally occurring steroids such as the ovarian steroid progesterone and the adrenal steroid deoxycorticosterone (DOC) can exert anesthetic and anticonvulsant actions.3 Recognizing that some steroids could produce such acute central nervous system effects, research at the pharmaceutical company Glaxo identified the synthetic steroid alphaxolone as having anesthetic properties. In the early 1970s, alphaxolone was marketed as a component of the intravenous anesthetic agent Althesin, which also included the less potent anesthetic steroid alphadalone acetate that was said to increase the solubility of alphaxolone.4 Several years later, the mechanism of action of alphaxolone was defined: it was found to enhance synaptic inhibition via an action on GABAA receptors.5,6 A major advance occurred when naturally occurring metabolites of progesterone and DOC were also found to enhance and directly activate GABAA receptors.7 It was speculated that the anesthetic and hypnotic properties of progesterone and DOC known since the time of Selye were due to their conversion in the body to these metabolites, respectively, allopregnanolone (3α-hydroxy-5α-pregnane-20-one) and allotetrahydrodeoxycorticosterone (3α,21-dihydroxy-5α-pregnan-20-one; THDOC). At the time, it was recognized that the enzymes required for the conversion of the steroid hormone precursors to their active A-ring reduced metabolites are present in brain so that part of the synthesis of the GABAA receptor active steroids could occur locally. Therefore, the neuroactive steroids allopregnanolone and THDOC came to be referred to as neurosteroids even though it was not believed at the time that their synthesis occurred independently of peripherally synthesized precursor steroid hormones. We now know that all of the enzymes required for the synthesis of the GABAA receptor active steroids from cholesterol are present in the brain.8 It is well recognized that these steroids readily cross the blood-brain barrier. While it is likely that locally synthesized GABAA receptor active steroids play a role in modulating circuit excitability, there is little information on the relative importance of de novo local synthesis versus peripheral production of either the active GABAA receptor modulatory steroids (e.g., allopregnanolone or THDOC) or their precursor hormones (e.g., progesterone or DOC) which are converted locally by brain 5α-reductase and 3α-hydroxysteroidoxidoreductase (3α-HSOR). Nevertheless, it is common to refer to GABAA receptor modulatory steroids such as allopregnanolone and THDOC as neurosteroids and we will follow that practice here. This chapter reviews the potential roles of such neurosteroids as endogenous modulators of seizure susceptibility and also the more limited evidence that they can under certain circumstances influence epileptogenesis (transformation of the brain to an epileptic state). The discussion of these topics serves as a prelude to the main objective of this chapter, which is to review the evidence supporting the utility of exogenously administered neurosteroid-related agents in the treatment of epilepsy.

DIVERSITY OF NEUROSTEROIDS AND THEIR BIOSYNTHESIS

A variety of GABAA receptor modulatory neurosteroids are known to be synthesized endogenously (Figures 1 and 2). The best recognized of these are the pregnane neurosteroids allopregnanolone and THDOC that are produced via sequential A-ring reduction of the steroid hormones progesterone and its 21-hydroxylated derivative deoxycorticosterone by 5α-reductase and 3α-HSOR isoenzymes. In the periphery, the steroid precursors are mainly synthesized in the gonads, adrenal gland, and feto-placental unit, but as noted above, synthesis of both of these neurosteroids likely occurs in the brain from cholesterol or from peripherally derived intermediates including the steroid hormone precursors. A-ring reduction can also occur in peripheral tissues such as reproductive endocrine tissues, liver, and skin that are rich in the two reducing activities.8 Since neurosteroids are highly lipophilic and can readily cross the blood-brain barrier, neurosteroids synthesized in peripheral tissues accumulate in the brain and can influence brain function.

Figure 1. Biochemical pathways of neurosteroid biosynthesis.

Figure 1

Biochemical pathways of neurosteroid biosynthesis. Cholesterol is trafficked by StAR (sterodogenic acute regulatory protein) and TSPO (translocator protein 18 kDa) to the inner mitochondrial membrane where it is converted to pregnenolone by P450sc (cytochrome (more...)

Figure 2. General scheme of peripheral steroidogenesis showing side pathways for the production of known neurosteroids.

Figure 2

General scheme of peripheral steroidogenesis showing side pathways for the production of known neurosteroids. Steroids known to act on GABAA receptors in a similar fashion to the prototypic neurosteroids allopregnanolone and allotetrahydrodeoxycorticosterone (more...)

The 5β-isomers of allopregnanolone and THDOC have GABAA receptor modulatory activity that is only modestly less potent than the corresponding 5α-epimers.9 A steroid 5β-reductase enzyme is distributed widely in vertebrates, including in the gonads, liver and brain.10 However, whether progesterone or DOC is a substrate and the extent to which 5β-reduced epimers of allopregnanolone and THDOC are produced endogenously is unclear.

The androgenic steroid testosterone differs from progesterone by virtue of a 17-alcohol that replaces the 17-acetyl in progesterone. Testosterone is a substrate for both 5α-reductase and 5β-reductase isoenzymes. The product of 5α-reduction of testosterone, 5α-dihydrotestosterone, is hormonally more active than testostosterone itself. However, subsequent 3α-reduction leads to 5α-androstanediol (5α-androstane-3α,17β-diol), which is comparable in potency and efficacy to allopregnanolone as a GABAA receptor positive modulator.11 5α- and 5β-Androstanediol are further metabolized by 17β-hydroxysteroid dehydrogenase to androsterone and etiocholanolone, respectively, which are considered the major excreted metabolites of testosterone. These compounds and their conjugates are present at high concentrations. Androsterone and etiocholanolone also have GABAA receptor positive modulatory activity and represent endogenous neurosteroids.12 Collectively, the various GABAA receptor modulatory steroids that lack the pregnane 17β-ethyl moiety, such as 5α-androstanediol, androsterone and etiocholanolone can be considered androstane neurosteroids. Finally, substantial amounts of androstenol, the 16-unstaturated form of 5α-androstanediol, are present in mammals, including humans. This compound is considered to be a pheromone that increases sexual receptivity in pigs and possibly other species. Androstenol also is a GABAA receptor positive modulator that has similar efficacy but is modestly less potent than allopregnanolone.13

PRODUCTION OF NEUROSTEROIDS IN THE BRAIN AND THEIR LOCALIZATION TO PRINCIPAL NEURONS

In addition to peripheral production, it is clear that neurosteroids can be formed from steroid hormone precursors (such as progesterone, DOC and perhaps testosterone) locally in the brain. 5α-Reductase activity has been identified in both neurons and glial cells in rodent and sheep brain, in regions, such as the neocortex and hippocampus, that are relevant to epilepsy.14,15 3α-HSOR is also expressed widely in the brain.16 In humans, both enzymes have been found in neocortex and hippocampus.17–19 Thus, it is likely that neurosteroids can be formed from their parent steroid hormone precursors directly in the brain. Steroid precursors readily enter the brain so that pools of peripherally synthesized precursors are available for local neurosteroid biosynthesis. In peripheral tissues 5α-reductase is believed to be the rate-limiting step in the production of neurosteroids because 3α-HSOR is a more ubiquitous enzyme; the same situation likely applies in brain.

It is likely that neurosteroids can be produced locally in brain not only from their steroid hormone precursors but also from more elementary steroid precursors such as cholesterol or pregnenolone. The rate-limiting and initial step in steroidogenesis is the conversion of cholesterol to pregnenolone by the mitochondrial enzyme P450scc (cytochrome P450 cholesterol side-chain cleavage enzyme; CYP11A). Access of cholesterol to P450scc requires StAR (steroidogenic acute regulatory protein), which functions to transfer cholesterol from the outer mitochondrial membrane to the inner membrane where P450scc is located.20 Translocator protein (18 kD) (TSPO), formerly called peripheral or mitochondrial benzodiazepine receptor, likely functions as a complex with StAR.21,22 Both proteins are expressed widely in peripheral tissues and in the brain. Activation of TSPO by certain ligands facilitates the intramitochondrial flux of cholesterol and thereby increases the availability of cholesterol to P450scc, enhancing pregnenolone synthesis and ultimately neurosteroid production.23,24 The observation that TSPO ligands enhance neurosteroid production not only confirms the key role of TSPO in neurosteroidogenesis, but suggests that such ligands may have therapeutic utility as an alternative to exogenously administered neurosteroids in situations where it is desirable to increase brain neurosteroids.25

In addition to P450scc, 3β-hydroxysteroid dehydrogenase, an enzyme required for the conversion of pregnenolone to progesterone, has been demonstrated in the brain.26 Thus, the enzymes necessary for in situ synthesis of progesterone from cholesterol are present in the brain.

In the adrenal, P450c21 (cytochrome P450 21-hydroxylase) converts progesterone to DOC, which is the precursor for the neurosteroid THDOC. The brain also possesses 21-hydroxylase activity, but it expresses only very small amounts of P450c21 mRNA and protein. It appears that CYP2D isoforms, in particular CYP2D4, present in brain can 21-hydroxylate progesterone to form DOC, which can then be converted to THDOC.27 In addition, allopregnanolone itself is a substrate for CYP2D4, so that in brain allopregnanolone may be converted directly to THDOC. Allopregnanolone and THDOC persist in the brain after adrenalectomy and gonadectomy or after pharmacological suppression of adrenal and gonadal steroid synthesis,28,29 confirming that these two key neurosteroids can be synthesized independently of peripherally produced steroid hormone precursors. However, the regulatory mechanisms underlying neurosteroid biosynthesis in the brain remain unclear.

In studies with mouse and rat brain, in situ hybridization with mRNA probes to 5α-reductase and 3α-HSOR indicates that the two mRNAs colocalize to glutamatergic principal neurons and not GABAergic inhibitory neurons or glial cells within neocortex, hippocampus, amygdala and other brain regions.30 Immunohistochemistry with an antiserum raised against allopregnanolone that also recognizes THDOC confirms that the neurosteroids are concentrated in principal neurons, predominantly in cell bodies and thick dendrites.31 The highly restricted distribution of neurosteroids to principal neurons suggests that they are mainly derived from local synthesis and not from the circulation, although it is clear that peripheral neurosteroids do readily cross the blood–brain barrier. It is remarkable that brain neurosteroids are localized to the neurons that contain their targets (GABAA receptors). This observation is consistent with the notion that neurosteroids function in an autocrine fashion in which they reach their targets by lateral membrane diffusion.32

NEUROSTEROID MODULATION OF GABAA RECEPTORS

In electrophysiological studies, allopregnanolone and THDOC at aqueous concentrations in the range 10–1500 nM enhance the activation of GABAA receptors by GABA.9,33 At higher concentrations, the steroids directly activate the receptor in the absence of GABA. In addition, like other positive allosteric modulators of GABAA receptors, neurosteroids exert allosteric effects on these receptors such that there is enhancement of the binding of [3H]flunitrazepam, a benzodiazepine receptor agonist, and [3H]muscimol, a specific GABA-site agonist; and inhibition of the binding of [35S]t-butylbicycloorthobenzoate (TBPS), a cage convulsant and noncompetitive GABAA receptor antagonist.34,35 Neurosteroid enhancement of GABAA receptors occurs through increases in both the channel open frequency and channel open duration.36–38 Thus, neurosteroids greatly enhance the probability of GABAA receptor chloride channel opening, thereby enhancing GABAA receptor mediated inhibition.

The effects of neurosteroids on GABAA receptors occurs by binding to discrete sites on the receptor-channel complex that are located within the transmembrane domains of the α- and β-subunits.38 The binding sites for neurosteroids are distinct from the recognition sites for GABA, benzodiazepines and barbiturates. Although the exact location of neurosteroid binding has not been mapped, it has been proposed that there are two distinct sites for neurosteroids that act as positive modulators: one for allosteric enhancement of GABA and another for direct activation of the receptor.37,38 Using site-directed mutagenesis, it has been shown that a highly conserved glutamine at position 241 in the M1 domain (toward the intracellular side) of the α-subunit plays a key role in neurosteroid modulation of GABA responses and is believed to contribute to the binding site for modulation.39 Additional nearby residues in the M4 domain of the same α-subunit (tyrosine 410 and asparagines 407, which are located more toward the extracellular side) have also been proposed to contribute to the binding site. Other investigators have found that mutations in serine 240 and tryptophan 245 of the α-subunit interfere with neurosteroid potentiation.40 Studies with structurally diverse steroids have led to the conclusion that the steroid binding pocket on the α-subunit is more correctly viewed as a “hydrophobic surface” that can accommodate steroid molecules of differerent structures.40 Direct activation of the receptor, in contrast, has been proposed to be due to binding at a site on the interface between β and α subunits formed by a threonine at position 236 in the α-subunit and a tyrosine at position 284 in the β-subunit.38 However, more recent models of the GABAA receptor have questioned whether these residues reside at β subunit–α subunit interface.41 A photo-incorporable analog of the anesthetic etomidate appears to bind at the interface but binding of this ligand is not competitively inhibited by neurosteroids.41 In fact, neurosteroids (at concentrations that produce direct receptor activation) enhance binding, presumably due to allosteric effects transmitted upon interaction with a different site on the receptor. The newer topology models do not bring into proximity the residues in the β- and α-subunits proposed to constitute the site for direct activation. Therefore, at present, the location of this site is uncertain.

A range of steroid structures have activity as positive modulators of GABAA receptors in line with the hydrophobic surface binding site model. Nevertheless, there are certain strict structural requirements for neurosteroid positive modulation. A hydrogen bond-donating 3α-hydroxy group on the steroid A-ring and a hydrogen bond accepting group (typically a keto moiety) on the D ring at either C20 of the pregnane steroid side chain or C17 of the androstane ring system are critical for positive modulatory activity at GABAA receptors.37,42 The orientation of the C5 hydrogen group only modestly influences potency.9

Studies with recombinant GABAA receptor isoforms indicate that neurosteroids act on most subunit combinations.37,43 This distinguishes neurosteroids from benzodiazepines, which only act on GABAA receptors that contain γ2 subunits and do not contain α4 or α6 subunits. In general, the specific α-subunit type may influence neurosteroid efficacy, whereas the γ subunit type may affect both the efficacy and potency of neurosteroid modulation.37

GABA is a relatively low-efficacy agonist of GABAA receptors in which the δ subunit replaces the more common γ2 subunit, even though it binds with high affinity to such δ-subunit-containing receptors.44 Neurosteroids therefore have an opportunity to markedly enhance the current generated by δ-subunit-containing GABAA receptors even in the presence of saturating GABA concentrations. Consequently, GABAA receptors that contain the δ subunit are highly sensitive to neurosteroid-induced potentiation of GABA responses45,46 and mice lacking δ-subunits show drastically reduced sensitivity to neurosteroids.47–49 GABAA receptors containing δ-subunits exhibit low desensitization and they are located nonsynaptically (perisynaptically/extrasynaptically) since the γ2 subunit is required for synaptic targeting. These properties cause them to be prime candidates for mediating ‘tonic’ GABAA receptor current that is activated by ambient concentrations of GABA in the extracellular space. Ambient GABA is believed to result from spillover of synaptically-released GABA; concentrations would increase with high levels of activity of GABAergic interneurons as occurs during seizures. Tonic GABAA receptor current causes a steady inhibition of neurons and reduces their excitability. Neurosteroids could therefore have a general role in setting the level of excitability and might specifically potentiate tonic inhibition during seizures when ambient GABA may rise. Overall, the robust effect of neurosteroids is likely to be due to their action on both synaptic and perisynaptic/extrasynaptic GABAA receptors.

Although neurosteroids are viewed as high-potency modulators of GABAA receptors since they are effective at concentrations in the mid-nanomolar to low micromolar range in aqueous solution, recent studies indicate that neurosteroid binding to the GABAA receptor is actually of low affinity (Kd, ~1 mM).32 The high effective potency of neurosteroids results from partitioning of the lipophilic steroids within the plasma membrane, such that the concentrations presented to the receptor are orders of magnitude greater. Neurosteroids access the GABAA receptor from the lipophilic plasma membrane. The non-specific accumulation and removal of the neurosteroids from the membrane are the major factors determining the rates of neurosteroid action when applied to cells via aqueous solution; rates of binding and unbinding to the receptor are only secondary factors.50 It is noteworthy that intracellular delivery through the plasma membrane is compatible with the autocrine mechanism discussed above where the neurosteroids act on the GABAA receptors in the same neurons in which they are produced.

As noted, at high concentrations (>10 μM), neurosteroids can directly receptor activate GABAA channels in the absence of GABA.9,51,52 In this respect, neurosteroids resemble barbiturates but not benzodiazepines.53 Given the high concentrations required, whether direct actions are relevant to the role of endogenous neurosteroids or to the pharmacological actions of exogenously administered neurosteroid-related agents is not well understood.

ANTICONVULSANT AND ANTIEPILEPTOGENIC EFFECTS OF NEUROSTEROIDS

Exogenously administered neurosteroids, like other agents that act as positive GABAA receptor modulators, exhibit broad-spectrum anticonvulsant effects in diverse rodent seizure models. They protect against seizures induced by GABAA receptor antagonists including pentylenetetrazol (PTZ) and bicuculline and they are effective against pilocarpine-induced limbic seizures and seizures in kindled animals.9,54–57 However, neurosteroids may exacerbate generalized absence seizures.58,59 The potencies of neurosteroids in models where they confer seizure protection vary largely in accordance with their activities as positive allosteric modulators of GABAA receptors. Thus, allopregnanolone has roughly equal potency to THDOC, but androstanediol, androsterone and etiocholanolone are somewhat less potent.12,60,61 Like other anticonvulsant agents that act on GABAA receptors, neurosteroids are inactive or only weakly active against electrically induced tonic extension seizures elicited according to the maximal electroshock (MES) protocol that is widely used for drug screening. However, they are active in the 6-Hz model in mice in which limbic-like seizure are induced by electrical stimulation of lower frequency and longer duration than in the MES test.62 In general, neurosteroids have comparable potencies in the 6-Hz and PTZ models. Neurosteroids are also highly effective in suppressing seizures due to withdrawal of GABAA receptor modulator drugs including neurosteroids and benzodiazepines (diazepam), and also due to other types of agents such as ethanol, which may act in part through GABAA receptors.63–65 In constrast to benzodiazepines where utility in the chronic treatment of epilepsy is limited by tolerance, anticonvulsant tolerance is not obtained with neurosteroids.66,67 Thus, neurosteroids have the potential to be used in the chronic treatment of epilepsy and this has been borne out in clinical trials (see below). The mechanisms responsible for tolerance to benzodiazepines are not known. However, factors such as uncoupling of the allosteric linkage between the GABA and benzodiazepine sites and changes in receptor subunit turnover with switching of subunits may be contributing mechanisms.68 Neurosteroids do not act on the benzodiazepine site of GABAA receptors, and they are able to modulate all isoforms of GABAA receptors, even those that contain benzodiazepine-insensitive α4 and α6 subunits or do not include the obligatory γ2 subunit required for benzodiazepine-sensitivity. Thus, it is clear that neurosteroids can act on GABAA receptors where the proposed benzodiazepine toleance mechanisms have been invoked. Surprisingly, while chronic neurosteroid exposure does not lead to anticonvulsant tolerance, chronic neurosteroid exposure does lead to tolerance to benzodiazepines.67 Thus it appears that the same plastic changes that underlie benzodiazepine tolerance are brought into play by chronic neurosteroid exposure. However, neurosteroids, acting at distinct sites on GABAA receptors and exhibiting effects on the full range of GABAA receptor isoforms, do not exhibit anticonvulsant tolerance. Whether tolerance can occur to other pharmacological actions of neurosteroids remains to be determined.

The sulfated neurosteroids pregnenolone sulfate and dehydroepiandosterone sulfate, which act as GABAA receptor antagonists, are proconvulsant when administered at high doses into the brain, producing seizures and status epilepticus.69,70 Compelling evidence that such steroids exist endogenously in the brain is lacking and in any case it is unlikely that they exist at sufficiently high concentrations to exert proconvulsant effects, so the physiological relevance is unclear. However, it is known that the seizure facilitating effects of these steroids can be blocked by coadministration of allopregnanolone or other neurosteroids that positively modulate GABAA receptors.71

In addition to anticonvulsant activity, there is some limited evidence that endogenous neurosteroids play a role in regulating epileptogenesis.72–74 Following pilocarpine-induced status epilepticus in the rat, the neurosteroidogenic enzyme P450scc is upregulated for several weeks, suggesting that neurosteroidogenesis may be increased. Ordinarily rats develop spontaneous recurrent seizures following a latent period of similar duration to the period during which P450scc is elevated. Inhibiting neurosteroid synthesis with finasteride, accelerated the onset of spontaneous recurrent seizures, suggesting that endogenous neurosteroids play a role in restraining epileptogenesis or at least that they inhibit the expression of seizures. Exogenous treatment with neurosteroids or with progesterone, which serves as a precursor for neurosteroid synthesis, has also been reported to delay the occurrence of epileptogenesis in some situations.75 In fact, progesterone may impair epileptogenesis in kindling models, even at doses that do not affect seizure expression.76,77 If endogenous neurosteroids can be confirmed as endogenous regulators of epileptogenesis, neurosteroids themselves or modulators of neurosteroid disposition could potentially have disease-modifying therapeutic activity.

ROLE OF ENDOGENOUS NEUROSTEROIDS IN THE MODULATION OF SEIZURES

Endogenous neurosteroids may play a role in the physiological regulation of seizure susceptibility in individuals with epilepsy. We will discuss several such situations: catamenial epilepsy, stress, temporal lobe epilepsy, and alcohol withdrawal. However, it is noteworthy that there is no evidence that alterations in neurosteroid levels in the absence of preexisting epilepsy can induce epileptogenesis.

Neurosteroids in Catamenial Epilepsy

Catamenial epilepsy, the cyclical occurrence of seizure exacerbations during particular phases of the menstrual cycle in women with preexisting epilepsy, is a specific form of pharmacoresistant epilepsy. Catamenial seizure exacerbations affect up to 70% of women of child-bearing age with epilepsy.78–80 Although there are several forms of catamenial epilepsy, neurosteroids have been implicated only in the seizure exacerbations that occur in the most common situation, which is when women with normal menstrual cycles experience seizure exacerbations in the perimenstrual period. It is hypothesized that withdrawal of progesterone-derived neurosteroids leads to enhanced brain excitability predisposing to seizures.

During the menstrual cycle, circulating progesterone levels are low in the follicular phase but rise in the midluteal phase for about 10 to 11 days, before declining in the late luteal phase. Circulating allopregnanolone levels parallel those of its parent progesterone.81 Circulating THDOC levels also fluctuate during the menstrual cycle, with higher levels in the luteal phase.81 Overall, the serum levels of THDOC are lower than those of allopregnanolone so that it is likely to be less relevant to catamenial epilepsy, although it could contribute. An important unanswered question is whether the local brain synthesis of neurosteroids also fluctuates.

In addition to withdrawal of the anticonvulsant effects of neurosteroids in association with the fall in progesterone at the time of menstruation, plasticity in GABAA receptors, the targets of neurosteroid action, could also play a role in the enhanced brain excitability that is presumed to underlie the increase in seizure susceptibility in perimenstrual catamenial epilepsy. The precise changes in brain GABAA receptor subunit expression occurring during the human menstrual cycle have not been determined. However, it is now well recognized that prolonged exposure to allopregnanolone in rats causes increased expression of the α4 GABAA receptor subunit in hippocampus resulting in decreased benzodiazepine sensitivity of GABAA receptor currents.82,83 Although α4 can coassemble with γ2 to form synaptic GABAA receptors, it preferentially coassembles with δ to form nonsynaptic (perisynaptic/extrasynaptic) GABAA receptors. Treatment of rats with allopregnanolone results in transient increased expression of the δ subunit in hippocampus and increased benzodiazepine-insensitive tonic current.84,85 Progesterone also increases δ subunit expression, likely as a result of conversion to allopregnanolone. The relevance of the increased δ subunit expression for catamenial epilepsy is unclear as δ subunit increases may be transitory and followed by reduced expression with chronic exposures as in pregnancy or in the prolonged luteal phase of the human menstrual cycle. Therefore, an important consequence of the incorporation of the normally low abundance α4 subunit into synaptic GABAA receptors is that synaptic currents generated by these receptors have accelerated decay kinetics, so that there is less total charge transfer, which results in reduced inhibition.86 GABAA receptor modulating neurosteroids cause a prolongation of the decay of GABA-mediated synaptic currents. Consequently, in the presence of high levels of allopregnanolone during the luteal phase, the acceleration due to α4 substitution is balanced. However, when neurosteroids are withdrawn at the time of menstruation, synaptic inhibition is diminished from normal, resulting in enhanced excitability, which, among other effects, predisposes to seizures. Indeed, chronic exposure to neurosteroids also is accompanied by downregulation of δ subunit expression and perisynaptic/extrasynaptic GABAA receptors.84 This change is believed to be a compensatory mechanism, which would avoid excessive sedation caused by high neurosteroid levels acting on sensitive δ subunit-containing GABAA receptors. At the time of neurosteroid withdrawal, δ subunit expression rapidly recovers. However, if recovery is not sufficiently fast, there could be an enhancement of excitability due to a reduction in tonic inhibition mediated by perisynaptic/extrasynaptic GABAA receptors in the relative absence of neurosteroids.

A rodent model has been developed to simulate the hormonal changes that are believed to be relevant to perimenstrual catamenial epilepsy.87,88 Rodents have a 4 to 5 day estrous cycle and studies of fluctuations in seizure susceptibility in cycling female rodents have not led to results that are relevant to the human menstrual cycle. In order to provide a model that more closely mimics the human situation, a condition of pseudopregnancy was induced in rats by sequential gonadotrophin treatment. This resulted in prolonged high circulating levels of estrogen and progesterone similar to those that occur in the luteal phase of the 28-day human menstrual cycle. Then, to simulate the withdrawal of allopregnanolone that occurs in conjunction with the fall in progesterone levels at the time of menstruation, the animals were treated with finasteride 11 days after the initiation of gonadotrophin treatment.

The neurosteroid withdrawal model of catamenial epilepsy was used to investigate therapies for perimenstrual catamenial epilepsy.63,89 A key result is that conventional antiepileptic drugs, including benzodiazepines and valproate, have reduced potency in protecting against seizures during the period of enhanced seizure susceptibility following neurosteroid withdrawal. This pharmacoresistance seems to mimic the situation in women with catamenial epilepsy where breakthrough seizures occur despite treatment with antiepileptic drugs. In contrast to the results with conventional antiepileptic drugs, neurosteroids, including allopregnanolone, THDOC and their 5β-isomers, were found to have enhanced activity in the perimenstrual catamenial epilepsy model.63 This suggested a “neurosteroid replacement” approach to treat catamenial seizure exacerbations.88 A neurosteroid could be administered in a “pulse” prior to menstruation and then withdrawn, or continuously administered throughout the month. While intermittent administration at the time of increased seizure vulnerability is rational, continuous administration would avoid withdrawal of the therapeutic agent, which itself could predispose to seizures. This factor, as well as the practical difficulty many women experience predicting the time of their menstrual periods, suggests that continuous administration is preferred. The neurosteroid would be administered at low doses to avoid sedative side effects. Such low doses are expected to contribute little anticonvulsant activity during most of the menstrual cycle. Patients would still require treatment with conventional antiepileptic medications. However, during the period of enhanced seizure susceptibility at the time of menstruation, the increased potency of the neurosteroid would confer protection against perimenstrual seizure exacerbations. It is noteworthy that while the anticonvulsant activity of neurosteroids increases in conjunction with neurosteroid withdrawal, there is no corresponding increase in side effects (mainly sedation), at least as assessed by a measure of motor impairment.88 Therefore, enhanced side effects, which would negate the potential of the therapeutic approach, would not be expected to occur.

To determine whether the enhanced activity of neurosteroids is due to pharmacokinetic or pharmacodynamic factors, brain and plasma levels of the neurosteroid ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) (discussed below) were determined with a liquid chromatography-mass spectrometric method. Control and neurosteroid withdrawn animals received a single dose of ganaxolone (7 mg/kg, subcutaneously), resulting in an elevation in PTZ threshold that peaked at 30 min and returned to baseline at 120–180 min. Ganaxolone caused a markedly greater (1.8-fold) elevation of PTZ threshold in the withdrawn animals than in controls, indicating a greater sensitivity to the anticonvulsant effects of ganaxolone. Surprisingly, plasma and brain ganaxolone levels were reduced in withdrawn animals (69% of control levels). Adjusting for the reduced brain levels, the pharmacodynamic sensitivity to ganaxolone was enhanced 2.3-fold in the withdrawn animals compared with controls. There was a significant increase in clearance (CL) of ganaxolone in the withdrawn animals, which accounts for the reduced plasma and brain levels. Brain levels of ganaxolone reached a peak more slowly (Tmax-brain, ~30 min) than in plasma (Tmax-plasma, ~15 min); the Tmax-brain value corresponds with the peak elevation in seizure threshold. These studies confirmed the enhanced anticonvulsant activity of ganaxolone in the rat model of catamenial epilepsy. The enhanced activity occurs in the face of decreased plasma and brain ganaxolone levels, indicating a marked increase in pharmacodynamic sensitivity.

Recently, studies have been conducted with the catamenial epilepsy model in female rats that have experienced a prolonged bout of status epilepticus induced by lithium–pilocarpine treatment, resulting in a chronic epileptic state with spontaneous recurrent seizures.90 Epileptic animals in the catamenial epilepsy model exhibited about six seizures per day, each lasting approximately a minute. When neurosteroids were withdrawn by treatment with finasteride, an enormous (more than 10-fold) increase in seizure frequency was observed. In contrast, finasteride did not induce seizures in normal animals. However, it did induce an increase in seizures in epileptic rats that were not treated with gonadotrophins, albeit of smaller magnitude than in the pseudopregnant animals. The observation that inhibition of the synthesis of endogenous neurosteroids in nonepileptic animals did not lead to seizures indicates that neurosteroid reductions are not epileptogenic. This is consistent with the observation that finasteride does not cause seizures in humans who do not have epilepsy. Finasteride is used clinically for the treatment of benign prostatic hypertrophy and male pattern hair loss. Seizures have not been reported as an adverse event of the drug. While it is clear that finasteride does not provoke seizures in the general population, there are no prospective studies to determine whether inhibition of 5α-reductase by finasteride influences seizure susceptibility in individuals with epilepsy. There is a single anecdotal report of a woman with epilepsy taking finasteride for male pattern baldness who experienced an increase in seizure frequency and severity in association with finasteride use.91 The doses of finasteride used clinically are in the range of 1–5 mg per day, which is far less than the doses of 30–100 mg/kg used in rats to inhibit brain neurosteroid synthesis. Furthermore, in humans, finasteride is selective for the type 2 5α-reductase isoform and less active on the type 1 enzyme that is the isoform predominantly present in the brain. This selectivity is not observed with the rat enzymes. In sum, finasteride, as administered clinically in humans, probably does not block neurosteroidogenesis sufficiently to influence seizure susceptibility under most circumstances. Also, individuals with congenital 5α-reductase deficiency, caused by a mutation in the 5α-reductase type 2 gene (a condition with ambiguous genitalia), do not exhibit epilepsy. While neurosteroid reduction by itself does not lead to epilepsy, it is apparent that endogenous neurosteroids do modulate seizure susceptibility in epileptic animals. Moreover, neurosteroid withdrawal causes markedly greater seizure provocation in the catamenial epilepsy model, consistent with earlier studies demonstrating enhanced seizure susceptibility in acute seizure models.

Although it has been assumed that the effect of finasteride on seizure susceptibility is mediated through inhibition of peripheral neurosteroidogenesis, ovariectomized epileptic animals also exhibited large increases in seizure frequency following finasteride treatment, indicating that a major effect of the drug may be to influence neurosteroid synthesis in the brain.90 Whatever the site of action of finasteride, treatment with exogenous allopregnanolone was found to rapidly terminate the finasteride-induced exacerbation of seizures, providing additional evidence that the increase in seizure frequency is due to a finasteride-induced reduction in neurosteroids and not some other action of the drug. More importantly, it supports the concept that neurosteroid replacement may be useful in the treatment of seizures associated with neurosteroid fluctuations, such as catamenial epilepsy. In catamenial epilepsy, breakthrough seizures occur despite treatment with antiepileptic drugs. Previous studies (reviewed in ref. 88) and the new results from Lawrence et al.90 support the potential of neurosteroids as a novel treatment approach for these pharmacoresistant seizures.

Although neurosteroids seems to be the most direct approach to the treatment of catamenial epilepsy, there is only limited anecdotal data available to support their use.92 No neurosteroid is currently approved. In contrast, there is considerable support from human clinical trials for the use of adjunctive progesterone in the treatment of perimenstrual catamenial epilepsy.93 It is recommended that the hormone be administered during the entire second half of the menstrual cycle and tapered gradually as it is believed that abrupt discontinuation can result in rebound seizure exacerbation. Enthusiasm for the use of progesterone in the treatment of catamenial epilepsy had been tempered by the lack of data from adequately controlled clinical trials. However, the results of a recent 10-year multicenter prospective controlled trial provide further evidence buttressing the clinical use of progesterone in selected patients and support the neurosteroid withdrawal hypothesis of perimenstrual catamenial epilepsy discussed in this chapter.93a In this study, supplemental oral progesterone or placebo was administered during days 14–28 of 3 menstrual cycles in 294 women who finished a 3-cycle baseline seizure assessment phase. Overall, progesterone did not cause a statistically significant reduction in seizure frequency judged by responder rate (≥50 reduction in seizure frequency), the primary outcome measure of the study. However, a prespecified post hoc analysis showed a beneficial effect of progesterone in women with perimenstrual seizure exacerbations (increased seizure frequency during the period 3 days before to 3 days after onset of menstruation). The extent of the benefit increased as the level of perimenstrual exacerbation increased. A statistically significant effect of progesterone was achieved in those subjects who exhibited a ≥3-fold perimenstrual increase in seizure frequency (21% of women in the study had this degree of seizure exacerbation). The study suggests that adjunctive cyclic progesterone supplementation may be useful in women with drug refractory partial seizures who have substantial perimenstrual seizure exacerbations. Progesterone therapy in women may cause hormonal effects such as breakthrough vaginal bleeding and breast tenderness as well as weight gain, sedation and emotional depression. Neurosteroids, such as ganaxolone, have not been associated with such side effects and may ultimately prove to be superior as a treatment approach. In the treatment regimen used in the clinical trials, progesterone is administered only after cycle day 14 and is tapered and discontinued during days 26 to 28 as it is believed that starting earlier than mid-cycle would interfere with normal cycling and lead to irregular bleeding. An advantage of hormonally-inactive neurosteroids is that they can be administered throughout the cycle, simplifying the treatment regimen.

Neurosteroids and Stress-Induced Seizure Fluctuations

The availability of neurosteroids is increased during physiological stress. Stress results in the hypothalamic release of corticotropin-releasing hormone (CRH), which liberates ACTH from the anterior pituitary. Along with cortisol, ACTH also enhances the synthesis of adrenal DOC,94,95 which is released into the circulation and can serve as a precursor for synthesis of the neurosteroid DOC (Figure 1). In contrast to allopregnanolone, which is present in the brain even after adrenalectomy and gonadectomy, THDOC appears to be derived nearly exclusively from adrenal sources.96 Plasma and brain levels of THDOC and allopregnanolone rise rapidly following acute stress.52,98 Acute stressors such as swimming, foot shock or carbon dioxide exposure elicit an increase in allopregnanolone and THDOC concentrations in plasma and in brain.98,99 Plasma levels of THDOC normally fluctuate between 1 and 5 nM, but increase to 15–30 nM following acute stress and might reach 40–60 nM during pregnancy.97,101 In contrast, allopregnanolone levels during the third trimester of pregnancy typically reach 70–160 nM and have been measured as high as 220 nM.101

Stress-induced neurosteroids have been demonstrated to elevate seizure threshold.52 Stress induced seizure protection could be due to circulating neurosteroids synthesized in peripheral tissues or to those produced locally in the brain. However, the effects of swim stress-induced increases in seizure threshold and THDOC levels in rats were abolished in adrenalectomized animals, implicating adrenal-derived THDOC. Despite stress-induced seizure protection in animals, 52,102 patients and clinicians are not likely to recognize a reduction in seizure frequency associated with stress. Indeed, stress has been reported to trigger seizure activity in persons with epilepsy.103,104 During stressful episodes adrenal hormone levels are expected to fluctuate and it may simply be the withdrawal of THDOC during such fluctuations that is associated with seizure provocation. Alternatively, other unidentified hormonal factors with proconvulsant activity may be responsible for stress-induced increases in seizures. However, chronic stress of the type experienced by patients with epilepsy likely has different endocrinological consequences than acute stress. The effects on seizures of fluctuations in neurosteroids in chronic stress remain to be studied.

Neurosteroids in Temporal Lobe Epilepsy

Sexual and reproductive dysfunction are common among persons with epilepsy.105 In particular, men with temporal lobe epilepsy (TLE) often have diminished libido and sexual potency that is associated with low testosterone levels.106–108 This hypogonadal state has been attributed to the effects of certain hepatic enzyme-inducing antiepileptic drugs, or alternatively—given the extensive connections between temporal lobe structures such as the amygdala and hypothalamic nuclei that govern the production and secretion of gonadotrophin releasing hormone—to suppression of the hypothalamic-pituitary-gonadal axis by limbic seizures. There is evidence that serum androgens normalize after temporal lobe surgery that results in successful seizure control but not in those that continue to have seizures, supporting the view that seizures are responsible for the hypoandrongenic state.109 Testosterone, as noted previously, is a precursor for at least three neurosteroids with anticonvulsant properties: 5α-androstanediol, androsterone and etiocholanolone.11,12,110,111 There is evidence that serum levels of at least two of these steroids (androsterone and etiocholanolone) are reduced in men with epilepsy compared with control subjects.106 It is conceivable that reduced levels of such anticonvulsant neurosteroids leads to enhanced propensity for seizures and that neurosteroid replacement might be a useful therapeutic approach.

Certain biological factors in temporal lobe epilepsy may influence the sensitivity to endogenous neurosteroids and could have an impact on the efficacy of exogenous neurosteroids used in epilepsy therapy. Studies in a status epilepticus model of TLE have shown a striking reduction in δ-subunit containing GABAA receptors in the dentate gyrus,112,113 suggesting that neurosteroid effects on nonsynaptic GABAA receptors may be reduced. In addition, in dentate gyrus granule cells neurosteroid modulation of synaptic currents is diminished and α4 subunit-containing receptors are present at synapses.114 All of these changes may facilitate seizures in epileptic animals but may reduce the efficacy of endogenous neurosteroids. The expression of neurosteroidogenic enzymes such as P450scc73 and 3α-HSOR17,19 appears to be elevated in the hippocampus in animals and human subjects affected by TLE. If local neurosteroidogenesis is enhanced, this may counteract in part the epileptogenesis-induced changes. However, the effect of withdrawal of neurosteroids as might occur in catamenial epilepsy or with stress could be enhanced.

Neurosteroids and Alcohol Withdrawal Seizures

Systemic administration of moderate doses (1–2.5 g/kg) of ethanol causes increases in plasma and brain neurosteroids that may contribute to many of the behavioral effects of ethanol in rodents.115 This effect of ethanol is believed to be due to activation of the hypothalamic-pituitary-adrenal axis. As is the case in the catamenial epilepsy model, chronic ethanol-induced elevations in neurosteroids lead to an enhancement in the anticonvulsant actions of the neurosteroids allopregnanolone and THDOC.116 These effects are associated with increases in the sensitivity of GABAA receptors to neurosteroids.115 Endogenous neurosteroids may protect against ethanol withdrawal seizures. However, ethanol induction of allopregnanolone is diminished in tolerant and dependent animals. Reduced availability of allopregnanolone under such circumstances may be a factor that predisposes to alcohol withdrawal seizures. As is the case with catamenial epilepsy, neurosteroid replacement could conceivably be useful in the treatment of alcohol withdrawal seizures, given that current pharmacological approaches are not entirely satisfactory.117

GANAXOLONE AS A NOVEL NEUROSTEROID-BASED ANTIEPILEPTIC DRUG

Ganaxolone, the synthetic 3β-methyl derivative of allopregnanolone,118 is the only neurosteroid that has been evaluated for the treatment of epilepsy in humans.75,119 Allopregnanolne itself has been administered to humans at low doses intravenously (0.05–0.09 mg/kg) and found to be largely free of side effects except for sedation.120,121 However, it has been proposed that allopregnanolone can undergo back conversion by 3α-HSOR isoenzymes to a hormonally active intermediate (dihydroprogesterone).122 The 3β-methyl substituent of ganaxolone eliminates this back conversion, potentially avoiding hormonal side effects. Other than this theoretical advantage, ganaxolone has pharmacological properties similar to the natural neurosteroid from which it was derived.

Preclinical studies

Ganaxolone has protective activity in diverse rodent seizure models, including clonic seizures induced by the chemoconvulsants pentylenetetrazol, bicuculline, flurothyl, t-butylbicycloorthobenzoate, aminophylline; limbic seizures in the 6 Hz model; amygdala and cocaine-kindled seizures; and corneal kindled seizures (Table 1).62,67,123–126 In chronically treated rats, tolerance does not occur to the anticonvulsant activity of ganaxolone.67 In addition, a recent study in female amygdala kindled mice demonstrated suppression of behavioral and electrographic seizures with ED50 of 6.6 mg/kg.127

Table 1. Anticonvulsant Profile of Ganaxolone in Mouse Seizure Models.

Table 1

Anticonvulsant Profile of Ganaxolone in Mouse Seizure Models.

Animal pharmacokinetic studies have found that ganaxolone has a large steady-state volume of distribution (6.5, 7.0, 19.5 and 3.5 L/kg in mice, rats, rabbits and dogs, respectively) indicating that it distributes extensively into tissues.75 Studies with radioactive ganaxolone in rats have found that ganaxolone (and its metabolites) are concentrated in tissues including the brain (brain-to-plasma concentration ratio between 5 and 10). Ganaxalone is highly bound to human plasma proteins (>99%). It is extensively metabolized to at least 16 different compounds; the primary metabolite is 16α-hydroxyganaxolone, which likely results from the action of CYP3A4. This primary metabolite is inactive in the PTZ seizure model and is 25-fold weaker than ganaxolone in inhibiting [35S]TBPS binding. Ganaxolone is a CYP3A4 autoinducer in rodents but not dogs or humans; chronic exposure to high doses in female rats does cause liver hypertrophy. Metabolites of ganaxolone are eliminated in the urine (13–23%) and feces (65–76%) in rats and dogs; the corresponding values in male healthy volunteers is 25% and 69%. Because of its aqueous insolubility, orally administered ganaxolone is poorly absorbed. To provide more consistent bioavailability, the steroid has been administered as a submicron particulate suspension and in a proprietary solid formulation.

Animal safety studies have demonstrated little evidence of target organ or systemic toxicity with either single-dose or multiple-dose ganaxolone treatment. In studies on pre- and postnatal development in mice, rats and dogs, ganaxolone did not affect fetal implantation, viability, or growth and development from birth to weaning, and was not teratogenic. Genotoxicity tests have not demonstrated any mutagenic or clastogenic potential for ganaxolone. Oral administration of ganaxolone to conscious dogs at a dose of 10 mg/kg did not reveal changes in cardiovascular hemodynamics.

Clinical Safety and Efficacy Studies

Over the past decade, ganaxolone has been studied in various clinical trials to assess its efficacy and safety in the treatment of epilepsy. More than 900 subjects have received the drug at doses up to 1875 mg/day in adults and up to 54 mg/kg/day in children in Phase 1 normal volunteer studies, epilepsy trials, and also clinical trials for migraine. Single oral doses of 50–1600 mg in healthy volunteers results in peak plasma concentrations between 14 as high as 460 ng/ml. Overall, the drug is safe and well tolerated. The most common side effect is reversible dose-related sedation. One epilepsy trial used the inpatient presurgical study design in adults with partial seizures.128 A second study was an open-label, add-on trial in pediatric patient with a history of infantile spasms.129 A third study was an open-label nonrandomized, dose-escalation add-on trial in highly refractory pediatric and adolescent patients; 3 patients in this latter study were followed in an extension phase over 3.5 year.130 As discussed previously, there is limited anecdotal information supporting the efficacy of ganaxolone in the treatment of catamenial seizure exacerbations.92 Recently, a double-blind, randomized, placebo controlled study was completed in adults with partial seizures.75,131 A separate trial was completed in infantile spasms. In this study, there was no clear statistically significant treatment effect although some subjects did appear to demonstrate a treatment-related reduction in spasm clusters as assessed by 24 hour video-electroencephalographic recordings.

The adult trial included 147 subjects (100 females, 47 males), aged 18 to 69 years, with partial onset seizures with or without secondary generalization who were refractory to conventional antiepileptic drugs. Subjects were randomized in a 2:1 ratio to ganaxolone (1500 mg/day in 3 divided doses with a 300 nm nanosized ganaxolone suspension formulation) or placebo. Ganaxolone treatment produced an 18% decrease in mean weekly seizure frequency, compared with a 2% increase for placebo over the 10-week treatment period (p=0.014). Responder rates (proportions of subjects with greater than 50% reduction in seizures during the maintenance phase) were 26% for the ganaxolone group versus 13% for the placebo group. Of 131 completers, 94% entered a 104-week open-label extension study. Results from the open label extension phase indicated that ganaxolone maintains its efficacy over time. Thirty-eight subjects (30%) completed more than 52 weeks of treatment before the study was terminated for administrative reasons. Subjects previously randomized to ganaxolone (n=79) in the double-blind study had median improvement in weekly seizure frequency (compared to the baseline from the beginning of the double-blind study) of 14% while those randomized to placebo had median weekly seizure improvement of 35% (n=41). Twenty-four percent of all subjects met responder criteria (50% improvement) at endpoint, 29% having originally been randomized to placebo and 22% having been randomized to ganaxolone. Adverse events reported by at least 5% of patients, and at least twice as common in the ganaxolone group than the placebo group, were dizziness, fatigue (both 16% versus 8%) and somnolence (13% versus 2%). Seven percent of the subjects in the ganaxolone treatment group and 6% in the placebo group discontinued treatment due to adverse events. No new safety concerns were identified during extended treatment with ganaxolone in the open label extension phase.

CONCLUSIONS

Neurosteroids are endogenous modulators of neural excitability that are believed to have a role in the regulation of seizure susceptibility in the setting of preexisting epilepsy. Menstrual and stress related fluctuations in seizures may in part be related to changes in brain neurosteroid levels. In addition, men with TLE who have suppression of the hypothalamic-pituitary-gonadal axis may have a reduction in testosterone-derived neurosteroids that could worsen seizures.

Treatment with exogenously administered natural neurosteroids or synthetic analogs such as ganaxolone may be beneficial to treat partial seizures. Further studies are required to determine if neurosteroid replacement is a useful therapeutic approach for seizure exacerbations related to endogenous neurosteroid fluctutations, such as in catamenial epilepsy and stress. In the future, agents that influence the endogenous synthesis of neurosteroids, such as TSPO ligands, may find utility as an alternative to neurosteroids themselves in the treatment of epilepsy.24,132

ACKNOWLEDGMENTS AND DISCLOSURES

The original research described in this article was supported in part by the NIH grants NS051398 and NS052158 (to D.S.R.) and NIH intramural grants NS002877 and NS002732 (to M.A.R.) and the Epilepsy Therapy Project (to M.A.R.). D.S.R. declares no conflicts; M.A.R. is a consultant to Sage Therapeutics and a scientific founder and has served as consultant to Marinus Pharmaceuticals, the current sponsor of ganaxolone.

REFERENCES

1.
Baulieu EE. Steroid hormones in the brain: several mechanisms? In: Fuxe F, Gustafsson JA, Wetterberg L, editors. Steroid Hormone Regulation of the Brain. Oxford: Pergamon Press; 1981. pp. 3–14.
2.
Paul SM, Purdy RH. Neuroactive steroids. FASEB J. 1992;6:2311–2322. [PubMed: 1347506]
3.
Selye H. Anesthetics of steroid hormones. Proc Soc Exp Biol Med. 1941;46:116–121.
4.
Clarke RS, Dundee JW, Carson IW. Proceedings: A new steroid anaesthetic-althesin. Proc R Soc Med. 1973;66:1027–1030. [PMC free article: PMC1645602] [PubMed: 4148526]
5.
Scholfield CN. Potentiation of inhibition by general anaesthetics in neurones of the olfactory cortex in vitro. Pflugers Arch. 1980;383:249–255. [PubMed: 7190680]
6.
Harrison NL, Simmonds MA. Modulation of the GABA receptor complex by a steroid anaesthetic. Brain Res. 1984;323:287–292. [PubMed: 6098342]
7.
Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science. 1986;232(4753):1004–1007. [PubMed: 2422758]
8.
Do Rego JL, Seong JY, Burel D, Leprince J, Luu-The V, Tsutsui K, Tonon MC, Pelletier G, Vaudry H. Neurosteroid biosynthesis: enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides. Front Neuroendocrinol. 2009;30:259–301. [PubMed: 19505496]
9.
Kokate TG, Svensson BE, Rogawski MA. Anticonvulsant activity of neuroactive steroids: correlation with γ-aminobutyric acid-evoked chloride current potentiation. J Pharmacol Exp Ther. 1994;270:1223–1229. [PubMed: 7932175]
10.
Langlois VS, Zhang D, Cooke GM, Trudeau VL. Evolution of steroid-5α-reductases and comparison of their function with 5β-reductase. Gen Comp Endocrinol. 2010;166:489–497. [PubMed: 19686747]
11.
Reddy DS, Jian K. The testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAA receptors. J Pharmacol Exp Ther. 2010;334:1031–1041. [PMC free article: PMC2939675] [PubMed: 20551294]
12.
Kaminski RM, Marini H, Kim WJ, Rogawski MA. Anticonvulsant activity of androsterone and etiocholanolone. Epilepsia. 2005;46:819–827. [PMC free article: PMC1181535] [PubMed: 15946323]
13.
Kaminski RM, Marini H, Ortinski PI, Vicini S, Rogawski MA. The pheromone androstenol (5α-androst-16-en-3α-ol) is a neurosteroid positive modulator of GABAA receptors. J Pharmacol Exp Ther. 2006;317:694–703. [PubMed: 16415088]
14.
Melcangi RC, Poletti A, Cavarretta I, Celotti F, Colciago A, Magnaghi V, Motta M, Negri-Cesi P, Martini L. The 5α-reductase in the central nervous system: expression and modes of control. J Steroid Biochem Mol Biol. 1998;65:295–299. [PubMed: 9699883]
15.
Petratos S, Hirst JJ, Mendis S, Anikijenko P, Walker DW. Localization of p450scc and 5α-reductase type-2 in the cerebellum of fetal and newborn sheep. Dev Brain Res. 2000;123:81–86. [PubMed: 11020552]
16.
Khanna M, Qin KN, Cheng KC. Distribution of 3α-hydroxysteroid dehydrogenase in rat brain and molecular cloning of multiple cDNAs encoding structurally related proteins in humans. J Steroid Biochem Mol Biol. 1995;53:41–46. [PubMed: 7626489]
17.
Stoffel-Wagner B, Beyenburg S, Watzka MS, Blumcke I, Bauer J, Schramm J, Bidlingmaier F, Elger CE. Expression of 5α-reductase and 3α-hydroxisteroid oxidoreductase in the hippocampus of patients with chronic temporal lobe epilepsy. Epilepsia. 2000;41:140–147. [PubMed: 10691110]
18.
Stoffel-Wagner B. Neuroactive steroid metabolism in the human brain. Eur J Endocrinol. 2001;145:669–679. [PubMed: 11720889]
19.
Stoffel-Wagner B, Watzka M, Steckelbroeck S, Ludwig M, Clusmann H, Bidlingmaier F, Casarosa E, Luisi S, Elger CE, Beyenburg S. Allopregnanolone serum levels and expression of 5α-reductase and 3α-hydroxysteroid dehydrogenase isoforms in hippocampal and temporal cortex of patients with epilepsy. Epilepsy Res. 2003;54:11–19. [PubMed: 12742591]
20.
Jefcoate C. High-flux mitochondrial cholesterol trafficking, a specialized function of the adrenal cortex. J Clin Invest. 2002;110:881–890. [PMC free article: PMC151162] [PubMed: 12370263]
21.
Korneyev A, Pan BS, Polo A, Romeo E, Guidotti A, Costa E. Stimulation of brain pregnenolone synthesis by mitochondrial diazepam binding inhibitor receptor ligands in vivo. J Neurochem. 1993;61:1515–1524. [PubMed: 8397297]
22.
Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006;27:402–409. [PubMed: 16822554]
23.
Kita A, Furukawa K. Involvement of neurosteroids in the anxiolytic-like effects of AC-5216 in mice. Pharmacol Biochem Behav. 2008;89:171–178. [PubMed: 18201755]
24.
Rupprecht R, Rammes G, Eser D, Baghai TC, Schüle C, Nothdurfter C, Troxler T, Gentsch C, Kalkman HO, Chaperon F, Uzunov V, McAllister KH, Bertaina-Anglade V, La Rochelle CD, Tuerck D, Floesser A, Kiese B, Schumacher M, Landgraf R, Holsboer F, Kucher K. Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science. 2009;325(5939):490–493. [PubMed: 19541954]
25.
Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N, Groyer G, Adams D, Schumacher M. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov. 2010;9:971–988. [PubMed: 21119734]
26.
Guennoun R, Fiddes RJ, Gouezou M, Lombes M, Baulieu EE. A key enzyme in the biosynthesis of neuroactive steroids, 3β-hydroxysteroid dehydrogenase/Δ54-isomerase (3β-HSD), is expressed in rat brain. Mol Brain Res. 1995;30:287–300. [PubMed: 7637579]
27.
Kishimoto W, Hiroi T, Shiraishi M, Osada M, Imaoka S, Kominami S, Igarashi T, Funae Y. Cytochrome P450 2D catalyze steroid 21-hydroxylation in the brain. Endocrinology. 2004;145:699–705. [PubMed: 14563706]
28.
Purdy RH, Morrow AL, Moore PH Jr, Paul SM. Stress-induced elevations of γ-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci USA. 1991;88:4553–4557. [PMC free article: PMC51699] [PubMed: 1852011]
29.
Corpechot C, Young J, Calvel M, Wehrey C, Veltz JN, Touyer G, Mouren M, Prasad VV, Banner C, Sjovall J. Neuroactive steroids: 3α-hydroxy-5α-pregnan-20-one and its precursors in the brain, plasma and steroidogenic glands of male and female rats. Endocrinology. 1993;133:1003–1009. [PubMed: 8365352]
30.
Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A. Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc Natl Acad Sci USA. 2006;103:14602–14607. [PMC free article: PMC1600006] [PubMed: 16984997]
31.
Saalmann YB, Kirkcaldie MT, Waldron S, Calford MB. Cellular distribution of the GABAA receptor-modulating 3α-hydroxy, 5α-reduced pregnane steroids in the adult rat brain. J Neuroendocrinol. 2007;19:272–284. [PubMed: 17355317]
32.
Chisari M, Eisenman LN, Covey DF, Mennerick S, Zorumski CF. The sticky issue of neurosteroids and GABAA receptors. Trends Neurosci. 2010;33:299–306. [PMC free article: PMC2902671] [PubMed: 20409596]
33.
Harrison NL, Majewska MD, Harrington JW, Barker JL. Structure-activity relationships for steroid interactions with the γ-aminobutyric acidA receptor complex. J Pharmacol Exp Ther. 1987;241:346–353. [PubMed: 3033209]
34.
Gee KW, Bolger MB, Brinton RE, Coirini H, McEwen BS. Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action. J Pharmacol Exp Ther. 1988;246:803–812. [PubMed: 2841455]
35.
Lan NC, Gee KW, Bolger MB, Chen JS. Differential responses of expressed recombinant human γ-aminobutyric acidA receptors to neurosteroids. J Neurochem. 1991;57:1818–1821. [PubMed: 1655982]
36.
Twyman RE, Macdonald RL. Neuroactive steroid regulation of GABAA receptor single-channel kinetic properties of mouse spinal cord neurons in culture. J Physiol. 1992;456:215–245. [PMC free article: PMC1175679] [PubMed: 1338096]
37.
Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA. Neurosteroid modulation of GABAA receptors. Prog Neurobiol. 2003;71:67–80. [PubMed: 14611869]
38.
Hosie AM, Wilkins ME, Smart TG. Neurosteroid binding sites on GABAA receptors. Pharmacol Ther. 2007;116:7–19. [PubMed: 17560657]
39.
Hosie AM, Clarke L, da Silva H, Smart TG. Conserved site for neurosteroid modulation of GABAA receptors. Neuropharmacology. 2009;56:149–154. [PubMed: 18762201]
40.
Akk G, Li P, Bracamontes J, Reichert DE, Covey DF, Steinbach JH. Mutations of the GABA-A receptor α1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids. Mol Pharmacol. 2008;74:614–627. [PMC free article: PMC2701692] [PubMed: 18544665]
41.
Li G-D, Chiara DC, Cohen JB, Olsen RW. Neurosteroids allosterically modulate binding of the anesthetic etomidate to γ-aminobutyric acid type A receptors. J Biol Chem. 2009;284:11771–11775. [PMC free article: PMC2673245] [PubMed: 19282280]
42.
Purdy RH, Morrow AL, Blinn JR, Paul SM. Synthesis, metabolism, and pharmacological activity of 3α-hydroxy steroids which potentiate GABA-receptor-mediated chloride ion uptake in rat cerebral cortical synaptoneurosomes. J Med Chem. 1990;33:1572–1581. [PubMed: 2160534]
43.
Puia G, Santi M, Vicini S, Pritchett DB, Purdy RH, Paul SM, Seeburg PH, Costa E. Neuroactive steroids act on recombinant human GABAA receptors. Neuron. 1990;4:759–765. [PubMed: 2160838]
44.
Glykys J, Mody I. Activation of GABAA receptors: views from outside the synaptic cleft. Neuron. 2007;56:763–770. [PubMed: 18054854]
45.
Belelli D, Casula A, Ling A, Lambert JJ. The influence of subunit composition on the interaction of neurosteroids with GABAA receptors. Neuropharmacology. 2002;43:651–661. [PubMed: 12367610]
46.
Wohlfarth KM, Bianchi MT, Macdonald RL. Enhanced neurosteroid potentiation of ternary GABAA receptors containing the δ subunit. J Neurosci. 2002;22:1541–1549. [PubMed: 11880484]
47.
Mihalek RM, Banerjee PK, Korpi ER, Quinlan JJ, Firestone LL, Mi ZP, Lagenaur C, Tretter V, Sieghart W, Anagnostaras SG, Sage JR, Fanselow MS, Guidotti A, Spigelman I, Li Z, DeLorey TM, Olsen RW, Homanics GE. Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor δ subunit knockout mice. Proc Natl Acad Sci USA. 1999;96:12905–12910. [PMC free article: PMC23157] [PubMed: 10536021]
48.
Spigelman I, Li Z, Banerjee PK, Mihalek RM, Homanics GE, Olsen RW. Behavior and physiology of mice lacking the GABAA-receptor δ subunit. Epilepsia. 2002;43(Suppl 5):3–8. [PubMed: 12121286]
49.
Stell BM, Brickley SG, Tang CY, Farrant M, Mody I. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABAA receptors. Proc Natl Acad Sci USA. 2003;100:14439–14444. [PMC free article: PMC283610] [PubMed: 14623958]
50.
Chisari M, Eisenman LN, Krishnan K, Bandyopadhyaya AK, Wang C, Taylor A, Benz A, Covey DF, Zorumski CF, Mennerick S. The influence of neuroactive steroid lipophilicity on GABAA receptor modulation: evidence for a low-affinity interaction. J Neurophysiol. 2009;102:1254–1264. [PMC free article: PMC2724350] [PubMed: 19553485]
51.
Lambert JJ, Cooper MA, Simmons RD, Weir CJ, Belelli D. Neurosteroids: endogenous allosteric modulators of GABAA receptors. Psychoneuroendocrinology. 2009;34(Suppl 1):S48–58. [PubMed: 19758761]
52.
Reddy DS, Rogawski MA. Stress-induced deoxycorticosterone-derived neuroactive steroids modulates GABAA receptor function and seizure susceptibility. J Neurosci. 2002;42:3795–3805. [PubMed: 11978855]
53.
Rho JM, Donevan SD, Rogawski MA. Direct activation of GABAA receptors by barbiturates in cultured rat hippocampal neurons. J Physiol (Lond) 1996;497(Pt 2):509–522. [PMC free article: PMC1161000] [PubMed: 8961191]
54.
Belelli D, Bolger MB, Gee KW. Anticonvulsant profile of the progesterone metabolite 5α-pregnan-3α-ol-20-one. Eur J Pharmacol. 1989;166:325–329. [PubMed: 2792198]
55.
Frye CA. The neuroactive steroid 3α,5α-THP has anti-seizure and possible neuroprotective effects in an animal model of epilepsy. Brain Res. 1995;696:113–120. [PubMed: 8574658]
56.
Wieland S, Belluzzi JD, Stein L, Lan NC. Comparative behavioral characterization of the neuroactive steroids 3α-OH,5α-pregnan-20-one and 3α-OH,5β-pregnan-20-one in rodents. Psychopharmacology. 1995;118:65–71. [PubMed: 7597124]
57.
Reddy DS, Castenada DA, O’Malley BW, Rogawski MA. Antiseizure activity of progesterone and neurosteroids in progesterone receptor knockout mice. J Pharmacol Exp Ther. 2004;310:230–239. [PubMed: 14982969]
58.
Snead OC 3rd. Ganaxolone, a selective, high-affinity steroid modulator of the γ-aminobutyric acid-A receptor, exacerbates seizures in animal models of absence. Ann Neurol. 1998;44:688–691. [PubMed: 9778270]
59.
Citraro R, Russo E, Di Paola ED, Ibbadu GF, Gratteri S, Marra R, De Sarro G. Effects of some neurosteroids injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy. Neuropharmacology. 2006;50:1059–1071. [PubMed: 16631210]
60.
Reddy DS. Anticonvulsant activity of the testosterone-derived neurosteroid 3α-androstanediol. Neuroreport. 2004;15:515–518. [PubMed: 15094514]
61.
Reddy DS. Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3α-androstanediol and 17β-estradiol. Neuroscience. 2004;129:195–207. [PubMed: 15489042]
62.
Kaminski RM, Livingood MR, Rogawski MA. Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice. Epilepsia. 2004;45:864–867. [PubMed: 15230714]
63.
Reddy DS, Rogawski MA. Enhanced anticonvulsant activity of neuroactive steroids in a rat model of catamenial epilepsy. Epilepsia. 2001;42:303–310. [PubMed: 11442150]
64.
Tsuda M, Suzuki T, Misawa M. Modulation of the decrease in the seizure threshold of pentylenetetrazole in diazepam-withdrawn mice by the neuroactive steroid 5α-pregnan-3α,21-diol-20-one (alloTHDOC) Addiction Biol. 1997;2:455–460. [PubMed: 26735951]
65.
Devaud LL, Purdy RH, Finn DA, Morrow AL. Sensitization of γ-aminobutyric acidA receptors to neuroactive steroids in rats during ethanol withdrawal. J Pharmacol Exp Ther. 1996;278:510–517. [PubMed: 8768698]
66.
Kokate TG, Yamaguchi S, Pannell LK, Rajamani U, Carroll DM, Grossman AB, Rogawski MA. Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice. J Pharmacol Exp Ther. 1998;287:553–558. [PubMed: 9808680]
67.
Reddy DS, Rogawski MA. Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself. J Pharmacol Exp Ther. 2000;295:1241–1248. [PubMed: 11082461]
68.
Bateson AN. Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal. Curr Pharmaceut Design. 2002;8:5–21. [PubMed: 11812247]
69.
Kokate TG, Juhng KN, Kirkby RD, Llamas J, Yamaguchi S, Rogawski MA. Convulsant actions of the neuroactive steroid pregnenolone sulfate in mice. Brain Res. 1999;831:119–124. [PubMed: 10411990]
70.
Williamson J, Mtchedlishvili Z, Kapur J. Characterization of the convulsant action of pregnenolone sulfate. Neuropharmacology. 2004;46:856–864. [PMC free article: PMC2885607] [PubMed: 15033345]
71.
Reddy DS, Kulkarni SK. Proconvulsant effects of neurosteroid pregnenolone sulfate and dehydroepiandrosterone sulfate in mice. Eur J Pharmacol. 1998;345:55–59. [PubMed: 9593594]
72.
Biagini G, Baldelli E, Longo D, Pradelli L, Zini I, Rogawski MA, Avoli M. Endogenous neurosteroids modulate epileptogenesis in a model of temporal lobe epilepsy. Exp Neurol. 2006;201:519–524. [PubMed: 16780839]
73.
Biagini G, Longo D, Baldelli E, Zoli M, Rogawski MA, Bertazzoni G, Avoli M. Neurosteroids and epileptogenesis in the pilocarpine model: Evidence for a relationship between P450scc induction and length of the latent period. Epilepsia. 2009;50(Suppl 1):53–58. [PMC free article: PMC4873280] [PubMed: 19125849]
74.
Biagini G, Panuccio G, Avoli M. Neurosteroids and epilepsy. Curr Opin Neurol. 2010;23:170–176. [PMC free article: PMC4873277] [PubMed: 20160650]
75.
Nohria V, Tsai J, Shaw K, Rogawski MA, Pieribone VA, Farfel G. Ganaxolone. In: Bialer M, et al., editors. Epilepsy Res; Progress report on new antiepileptic drugs: a summary of the Tenth Eilat Conference (EILAT X); 2010. pp. 89–124. [PubMed: 20970964]
76.
Edwards HE, Mo V, Burnham WM, MacLusky NJ. Gonadectomy unmasks an inhibitory effect of progesterone on amygdala kindling in male rats. Brain Res. 2001;889:260–263. [PubMed: 11166716]
77.
Reddy DS, Gangisetty O, Briyal S. Disease-modifying activity of progesterone in the hippocampus kindling model of epileptogenesis. Neuropharmacology. 2010;59:573–573. [PMC free article: PMC2963708] [PubMed: 20804775]
78.
Herzog AG, Harden CL, Liporace J, Pennell P, Schomer DL, Sperling M, Fowler K, Nikolov B, Shuman S, Newman M. Frequency of catamenial seizure exacerbation in women with localization-related epilepsy. Ann Neurol. 2004;56:431–434. [PubMed: 15349872]
79.
Bazan AC, Montenegro MA, Cendes F, Min LL, Guerreiro CA. Menstrual cycle worsening of epileptic seizures in women with symptomatic focal epilepsy. Arg Neuropsiguiatr. 2005;63(3B):751–756. [PubMed: 16258650]
80.
Reddy DS. The role of neurosteroids in the pathophysiology and treatment of catamenial epilepsy. Epilepsy Res. 2009 Jul;85(1):1–30. [PMC free article: PMC2696558] [PubMed: 19406620]
81.
Tuveri A, Paoletti AM, Orrù M, Melis GB, Marotto MF, Zedda P, Marrosu F, Sogliano C, Marra C, Biggio G, Concas A. Reduced serum level of THDOC, an anticonvulsant steroid, in women with perimenstrual catamenial epilepsy. Epilepsia. 2008;49:1221–1229. [PubMed: 18325018]
82.
Gulinello M, Gong QH, Li X, Smith SS. Short-term exposure to a neuroactive steroid increases α4 GABAA receptor subunit levels in association with increased anxiety in the female rat. Brain Res. 2001;910:55–66. [PMC free article: PMC4170586] [PubMed: 11489254]
83.
Gangisetty O, Reddy DS. Neurosteroid withdrawal regulates GABAA receptor α4-subunit expression and seizure susceptibility by activation of progesterone receptor-independent early growth response factor-3 pathway. Neuroscience. 2010;170:865–880. [PMC free article: PMC2939139] [PubMed: 20670676]
84.
Shen H, Gong QH, Yuan M, Smith SS. Short-term steroid treatment increases δ GABAA receptor subunit expression in rat CA1 hippocampus: pharmacological and behavioral effects. Neuropharmacology. 2005;49:573–586. [PMC free article: PMC2887348] [PubMed: 15950994]
85.
Maguire JL, Stell BM, Rafizadeh M, Mody I. Ovarian cycle-linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci. 2005;8:797–804. [PubMed: 15895085]
86.
Smith SS, Gong QH. Neurosteroid administration and withdrawal alter GABAA receptor kinetics in CA1 hippocampus of female rats. J Physiol. 2005;564:421–436. [PMC free article: PMC1464432] [PubMed: 15705652]
87.
Reddy DS, Kim HY, Rogawski MA. Neurosteroid withdrawal model of perimenstrual catamenial epilepsy. Epilepsia. 2001;42:328–336. [PubMed: 11442149]
88.
Reddy DS, Rogawski MA. Neurosteroid replacement therapy for catamenial epilepsy. Neurotherapeutics. 2009;6:392–401. [PMC free article: PMC2682439] [PubMed: 19332335]
89.
Reddy DS, Rogawski MA. Enhanced anticonvulsant activity of ganaxolone after neurosteroid withdrawal in a rat model of catamenial epilepsy. J Pharmacol Exp Ther. 2000;294:909–915. [PubMed: 10945840]
90.
Lawrence C, Martin BS, Sun C, Williamson J, Kapur J. Endogenous neurosteroid synthesis modulates seizure frequency. Ann Neurol. 2010;67:689–693. [PMC free article: PMC2918659] [PubMed: 20437568]
91.
Herzog AG, Frye CA. Seizure exacerbation associated with inhibition of progesterone metabolism. Ann Neurol. 2003;53:390–391. [PubMed: 12601707]
92.
McAuley JW, Reeves Al, Flyak J, Monaghan EP, Data J. A pilot study of the neurosteroid ganaxolone in catamenial epilepsy: clinical experience in two patients. Epilepsia. 2001;42(Suppl 7):85 (1.267).
93.
Herzog AG. Hormonal therapies: progesterone. Neurotherapeutics. 2009;6:383–391. [PMC free article: PMC5084218] [PubMed: 19332334]
93a.
Herzog AG, Fowler KM, Smithson SD, Kalayjian LA, Heck CN, Sperling MR, Liporace JD, Harden CL, Dworetzky BA, Pennell PB, Massaro JM. Progesterone vs placebo therapy for women with epilepsy: A randomized clinical trial. Neurology. 2012;78:1959–1966. [PMC free article: PMC3369508] [PubMed: 22649214]
94.
Tan SY, Mulrow PJ. The contribution of the zona fasciculata and glomerulosa to plasma 11-deoxycorticosterone levels in man. J Clin Endocrinol Metab. 1075;41:126–130. [PubMed: 168227]
95.
Kater CE, Biglieri EG, Brust N, Chang B, Hirai J, Irony I. Stimulation and suppression of the mineralocorticoid hormones in normal subjects and adrenocortical disorder. Endocrine Rev. 1989;10:149–164. [PubMed: 2666117]
96.
Purdy RH, Morrow AL, Blinn JR, Paul SM. Synthesis, metabolism, and pharmacological activity of 3α-hydroxy steroids which potentiate GABA-receptor-mediated chloride ion uptake in rat cerebral cortical synaptoneurosomes. J Med Chem. 1990;33:1572–1581. [PubMed: 2160534]
97.
Concas A, Mostallino MC, Porcu P, Folesa P, Barbaccia ML, Trabucchi M, Purdy RH, Grisenti P, Biggio G. Role of brain allopregnanolone in the plasticity of γ-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery. Proc Natl Acad Sci USA. 1998;95:13284–13289. [PMC free article: PMC23784] [PubMed: 9789080]
98.
Barbaccia ML, Roscetti G, Trabucchi M, Mostallino MC, Concas A, Purdy RH, Biggio G. Time-dependent changes in rat brain neuroactive steroid concentrations and GABAA receptor function after acute stress. Neuroendocrinology. 1996;63:166–172. [PubMed: 9053781]
99.
Barbaccia ML, Roscetti G, Trabucchi M, Purdy RH, Mostallino MC, Concas A, Biggio G. The effects of inhibitors of GABAergic transmission and stress on brain and plasma allopregnanolone concentrations. Br J Pharmacol. 1997;120:1582–1588. [PMC free article: PMC1564614] [PubMed: 9113382]
100.
Vallee M, Rivera JD, Koob GF, Purdy RH, Fitzgerald RL. Quantification of neurosteroids in rat plasma and brain following swim stress and allopregnanolone administration using negative chemical ionization gas chromatography/mass spectrometry. Anal Biochem. 2000;287:153–166. [PubMed: 11078595]
101.
Parízek A, Hill M, Kancheva R, Havlíková H, Kancheva L, Cindr J, Pasková A, Pouzar V, Cerny I, Drbohlav P, Hájek Z, Stárka L. Neuroactive pregnanolone isomers during pregnancy. J Clin Endocrinol Metab. 2005;90:395–403. [PubMed: 15486056]
102.
Peričić D, Švob D, Jazvinšćak M, Mirković K. Anticonvulsive effect of swim stress in mice. Pharmacol Biochem Behav. 2000;66:879–886. [PubMed: 10973529]
103.
Temkin NR, Davis GR. Stress as a risk factor for seizures among adults with epilepsy. Epilepsia. 1984;25:450–456. [PubMed: 6745217]
104.
Frucht MM, Quigg M, Schwaner C, Fountain NB. Distribution of seizure precipitants among epilepsy syndromes. Epilepsia. 2000;41:1534–1539. [PubMed: 11114210]
105.
Edwards HE, MacLusky NJ, Burnham WM. Epileptic seizures: Do they cause reproductive dysfunction. Univ Toronto Med J. 2000:104–111.
106.
Brunet M, Rodamilans M, Martinez-Osaba MJ, Santamaria J, To-Figueras J, Torra M, Corbella J, Rivera F. Effects of long-term antiepileptic therapy on the catabolism of testosterone. Pharmacol Toxicol. 1995;76:371–375. [PubMed: 7479578]
107.
Herzog AG, Seibel MM, Schomer DL, Vaitukaitis JL, Geschwind N. Reproductive endocrine disorders in men with partial seizures of temporal lobe origin. Arch Neurol. 1986;43:347–350. [PubMed: 3082313]
108.
Herzog AG. Altered reproductive endocrine regulation in men with epilepsy: implications for reproductive function and seizures. Ann Neurol. 2002;51:539–542. [PubMed: 12112098]
109.
Bauer J, Stoffel-Wagner B, Flügel D, Kluge M, Schramm J, Bidlingmaier F, Elger CE. Serum androgens return to normal after temporal lobe epilepsy surgery in men. Neurology. 2000;55:820–824. [PubMed: 10994003]
110.
Reddy DS. Anticonvulsant activity of the testosterone-derived neurosteroid 3α-androstanediol. Neuroreport. 2004;15:515–518. [PubMed: 15094514]
111.
Reddy DS. Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3α-androstanediol and 17β-estradiol. Neuroscience. 2004;129:195–207. [PubMed: 15489042]
112.
Peng Z, Huang CS, Stell BM, Mody I, Houser CR. Altered expression of the δ subunit of the GABAA receptor in a mouse model of temporal lobe epilepsy. J Neurosci. 2004;24:8629–8639. [PubMed: 15456836]
113.
Zhang N, Wei W, Mody I, Houser CR. Altered localization of GABAA receptor subunits on dentate granule cell dendrites influences tonic and phasic inhibition in a mouse model of epilepsy. J Neurosci. 2007;27:7520–7531. [PubMed: 17626213]
114.
Sun C, Mtchedlishvili Z, Erisir A, Kapur J. Diminished neurosteroid sensitivity of synaptic inhibition and altered location of the α4 subunit of GABAA receptors in an animal model of epilepsy. J Neurosci. 2007;27:12641–12650. [PMC free article: PMC2878477] [PubMed: 18003843]
115.
Morrow AL, Porcu P, Boyd KN, Grant KA. Hypothalamic-pituitary-adrenal axis modulation of GABAergic neuroactive steroids influences ethanol sensitivity and drinking behavior. Dialogues Clin Neurosci. 2006;8:463–477. [PMC free article: PMC3181829] [PubMed: 17290803]
116.
Devaud LL, Purdy RH, Finn DA, Morrow AL. Sensitization of γ-aminobutyric acidA receptors to neuroactive steroids in rats during ethanol withdrawal. J Pharmacol Exp Ther. 1996;278:510–517. [PubMed: 8768698]
117.
N’Gouemo P, Rogawski MA. Alcohol withdrawal seizures. In: Pitkänen A, Schwartzkroin PA, Moshé SL, editors. Models of Seizures and Epilepsy. Amsterdam: Elsevier Academic Press; 2006. pp. 161–177.
118.
Carter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, White HS, Wolf HH, Mirsadeghi S, Tahir SH, Bolger MB, Lan NC, Gee KW. Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3α-hydroxy-3β-methyl-5α-pregnan-20-one), a selective, high-affinity, steroid modulator of the γ-aminobutyric acidA receptor. J Pharmacol Exp Ther. 1997;280:1284–1295. [PubMed: 9067315]
119.
Monaghan EP, McAuley JW, Data JL. Ganaxolone: a novel positive allosteric modulator of the GABAA receptor complex for the treatment of epilepsy. Expert Opin Investig Drugs. 1999;8:1663–1671. [PubMed: 11139818]
120.
Timby E, Balgård M, Nyberg S, Spigset O, Andersson A, Porankiewicz-Asplund J, Purdy RH, Zhu D, Bäckström T, Poromaa IS. Pharmacokinetic and behavioral effects of allopregnanolone in healthy women. Psychopharmacology (Berl) 2006;186:414–424. [PubMed: 16177884]
121.
Kask K, Bäckström T, Lundgren P, Sundström Poromaa I. Allopregnanolone has no effect on startle response and prepulse inhibition of startle response in patients with premenstrual dysphoric disorder or healthy controls. Pharmacol Biochem Behav. 2009;92:608–613. [PubMed: 19268499]
122.
Rupprecht R, Reul JM, Trapp T, van Steensel B, Wetzel C, Damm K, Zieglgansberger W, Holsboer F. Progesterone receptor-mediated effects of neuroactive steroids. Neuron. 1993;11:523–530. [PubMed: 8398145]
123.
Liptáková S, Velísek L, Velísková J, Moshé SL. Effect of ganaxolone on flurothyl seizures in developing rats. Epilepsia. 2000;41:788–793. [PubMed: 10897148]
124.
Rogawski MA, Reddy DS. Neurosteroids: endogenous modulators of seizure susceptibility. In: Rho JM, Sankar R, Cavazos J, editors. Epilepsy: Scientific Foundations of Clinical Practice. New York: Marcel Dekker New York; 2004. pp. 319–355.
125.
Gasior M, Ungard JT, Beekman M, Carter RB, Witkin JM. Acute and chronic effects of the synthetic neuroactive steroid, ganaxolone, against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled mice: comparison with diazepam and valproate. Neuropharmacology. 2000;39:1184–1196. [PubMed: 10760361]
126.
Kaminski RM, Gasior M, Carter RB, Witkin JM. Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice. Eur J Pharmacol. 2003;474:217–222. [PubMed: 12921865]
127.
Reddy DS, Rogawski MA. Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model. Epilepsy Res. 2010;89:254–260. [PMC free article: PMC2854307] [PubMed: 20172694]
128.
Laxer K, Blum D, Abou-Khalil BW, Morrell MJ, Lee DA, Data JL, Monaghan EP. Assessment of ganaxolone’s anticonvulsant activity using a randomized, double-blind, presurgical trial design. Ganaxolone Presurgical Study Group. Epilepsia. 2000;41:1187–1194. [PubMed: 10999558]
129.
Kerrigan JF, Shields WD, Nelson TY, Bluestone DL, Dodson WE, Bourgeois BF, Pellock JM, Morton LD, Monaghan EP. Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial. Epilepsy Res. 2000;42:133–139. [PubMed: 11074186]
130.
Pieribone VA, Tsai J, Soufflet C, Rey E, Shaw K, Giller E, Dulac O. Clinical evaluation of ganaxolone in pediatric and adolescent patients with refractory epilepsy. Epilepsia. 2007;48:1870–1874. [PubMed: 17634060]
131.
Farfel G, Tsai J, Shaw K, Nohria V, Rogawski MA. In: Bialer M, et al., editors. Epilepsy Res; Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI); in press.
132.
Dhir A, Rogawski MA. Role of neurosteroids in the anticonvulsant activity of midazolam. Br J Pharmacol. 2012;165:2684–2691. [PMC free article: PMC3423249] [PubMed: 22014182]
Copyright © 2012, Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen.

All Jasper's Basic Mechanisms of the Epilepsies content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported license, which permits copying, distribution and transmission of the work, provided the original work is properly cited, not used for commercial purposes, nor is altered or transformed.

Bookshelf ID: NBK98218PMID: 22787590

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this page (1.3M)
  • PDF version of this title (215M)

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...