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Epilepsy Research 44 (2001) 141– 153

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Neuroactive steroids and seizure susceptibility


Stefan Beyenburg a,*, Birgit Stoffel-Wagner b, Jürgen Bauer a,
Matthias Watzka a, Ingmar Blümcke c, Frank Bidlingmaier b,
Christian E. Elger a
a
Department of Epileptology, Uni6ersity of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany
b
Department of Clinical Biochemistry, Uni6ersity of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany
c
Department of Neuropathology, Uni6ersity of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany

Received 15 October 2000; received in revised form 15 January 2001; accepted 19 January 2001

Abstract

There is increasing clinical and experimental evidence that hormones, in particular sex steroid hormones, influence
neuronal excitability and other brain functions. The term ‘neuroactive steroids’ has been coined for steroids that
interact with neurotransmitter receptors. One of the best characterized actions of neuroactive steroids is the allosteric
modulation of GABAA-receptor function via binding to a putative steroid-binding site. Since neuroactive steroids
may interact with a variety of other membrane receptors, excitatory as well as inhibitory, they may have an impact
on the excitability of specific brain regions. Neuronal excitability is enhanced by estrogen, whereas progesterone and
its metabolites exert anticonvulsant effects. Testosterone and corticosteroids have less consistent effects on seizure
susceptibility. Apart from these particular properties, neuroactive steroids may regulate gene expression via proges-
terone receptors. Based on their molecular properties, these compounds appear to have a promising therapeutical
profile for the treatment of different neuropsychiatric diseases including epilepsy. This review focuses on the effects
of neuroactive steroids on neuronal excitability and their putative impact on the physiology of epileptic disorders.
© 2001 Elsevier Science B.V. All rights reserved.

Keywords: Neuroactive steroids; Neurosteroids; Neuronal excitability; Seizures; Epilepsy

1. Introduction epilepsy or juvenile myoclonic epilepsy — tempo-


rally corresponds to alterations in hormonal bal-
Hormones, particularly sex steroid hormones, ance during puberty. In women, changes in
influence the probability of seizure occurrence. hormones during the menstrual cycle, at puberty,
From a clinical point of view, the development of during pregnancy and menopause may influence
certain epilepsy syndromes — such as absence seizure frequency (Morrell, 1992, 1999; Herzog,
1999b,c). However, the mechanisms by which
* Corresponding author. Tel.: + 49-228-2875748; fax: + 49- steroid hormones modulate seizure vulnerability
228-2876294. are not yet fully understood.
E-mail address: s.beyenburg@uni-bonn.de (S. Beyenburg).

0920-1211/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 9 2 0 - 1 2 1 1 ( 0 1 ) 0 0 1 9 4 - 2
142 S. Beyenburg et al. / Epilepsy Research 44 (2001) 141–153

Steroid hormones are mainly synthesized in the tic disorders. Details of biosynthesis and
adrenal glands (mineralo- and glucocorticoids), metabolism of neuroactive steroids have been re-
gonads and the fetoplacental unit (sex hormones, viewed previously (Paul and Purdy, 1992; Majew-
i.e. androgens, estrogens and progesterone). Due ska, 1992; Mellon, 1994; Baulieu, 1998;
to their high lipid solubility, they cross the Mensah-Nyagan et al., 1999). Furthermore, recent
blood –brain barrier easily. The brain is regarded findings on the mRNA expression of neuros-
as a target for steroid actions because these hor- teroidogenic enzymes in the brains of patients
mones can affect neuroendocrine and behavioral with epilepsy are summarized. Fig. 1 shows im-
brain functions via binding to cytosolic intracellu- portant steps of neurosteroid biosynthesis.
lar receptors, thus activating the genome for tran-
scription and protein synthesis. The response to
these steroid actions is observed with a delay of 2. Neuroactive steroids and seizure susceptibility
hours to days (delayed, genomic actions) (Majew-
ska, 1992; Mellon, 1994; Lambert et al., 1995; 2.1. Sex hormones
Joels, 1997; Rupprecht and Holsboer, 1999a,b).
Apart from these actions, certain steroids and Several lines of evidence suggest that neuroac-
their metabolites alter neuronal excitability within tive steroids modulate seizure susceptibility. Early
seconds to minutes (fast, nongenomic actions). observations described the impact of estrogens on
The mechanism of this action is a modulation of the exacerbation of seizures in women with
the activity of a variety of neurotransmitter recep- epilepsy (Logothetis et al., 1959). Subsequent ex-
tors and ion channels on the cell surface, e.g. perimental studies confirmed the proconvulsant
g-aminobutyric acidA (GABAA) and N-methyl-D- effects of estrogens (Logothetis and Harner, 1960;
aspartate (NMDA) receptors (Majewska, 1992; Stitt and Kinnard, 1968). From a clinical point of
Mellon, 1994; Lambert et al., 1995; Joels, 1997; view, the influence of sex hormones on the occur-
Rupprecht and Holsboer, 1999a,b). For steroids rence of epileptic seizures is best documented in
with these properties, the term ‘neuroactive female patients exerting a perimenstrual increase
steroids’ has been coined (Paul and Purdy, 1992; of seizure frequency, i.e. catamenial seizures (Her-
Majewska, 1992; Mellon, 1994). Moreover, the zog et al., 1997). This gives rise to the hypothesis
brain is not only a target tissue for actions of that the physiological premenstrual decrease of
neuroactive steroids from peripheral sources, but progesterone and its metabolites exerts convulsive
may also produce steroids de novo from choles- effects and that catamenial seizures can be at-
terol. Such steroids have been defined as neuros- tributed to the neuroactive properties of steroids
teroids and include compounds such as (Reddy and Rogawski, 2000a). The clinical phe-
dehydroepiandrosterone (DHEA) and preg- nomenon of catamenial epilepsy is well docu-
nenolone, as well as their esters (DHEA sulfate mented, with varying incidence in the reported
and pregnenolone sulfate, respectively), proges- studies (Duncan et al., 1993; Herkes et al., 1993;
terone and the 5a-reduced progesterone metabo- Herzog et al., 1997; Bauer et al., 1998; Zahn,
lite, allopregnanolone (3a-OH-5a-pregnan-20-one, 1999; Penovich, 2000). The influence of steroid
3a,5a-tetrahydroprogesterone) (Baulieu, 1998; hormones on seizure occurrence also arises from
Mensah-Nyagan et al., 1999). In the brains of therapeutic regimen using progesterone: proges-
vertebrates, glial cells are the major site for neu- terone decreased perimenstrual seizure frequency
rosteroid formation and metabolism (Baulieu, in patients with luteal insufficiency (Herzog et al.,
1998). Recent studies demonstrated that these 1997) and cyclic adjunctive progesterone therapy
substances may also be synthesized by neurons led to improved seizure control in women with
(Tsutsui et al., 2000). anovulation (Herzog, 1999a,b). In women with
The present review focuses on the effects of focal epilepsy, intravenous infusion of proges-
neuroactive steroids on neuronal excitability and terone led to a significant decrease in spike fre-
their putative impact on the physiology of epilep- quency (Bäckström et al., 1984). Add-on therapy
S. Beyenburg et al. / Epilepsy Research 44 (2001) 141–153 143

Fig. 1. Biosynthesis and metabolism of neurosteroids. Enzymes indicated by asterisks are expressed in human brain. The broken
lines indicate that several steroids are omitted from the diagram in the formation of DHEA from pregnenolone and in the formation
of androstenedione from progesterone. Abbreviations: DHP, dihydroprogesterone; DHEA, dehydroepiandrosterone; DHEAS,
dehydroepiandrosterone sulfate; THP, tetrahydroprogesterone; DHDOC, dihydro-11-deoxycorticosterone; THDOC, tetrahydro-11-
deoxycorticosterone. P450scc, P450 side chain cleavage; P450 Arom, P450 Aromatase; HSD, hydroxisteroid oxidoreductase.
144 S. Beyenburg et al. / Epilepsy Research 44 (2001) 141–153

with cyclic natural progesterone resulted in a sig- hart, 1993; Mensah-Nyagan et al., 1999; Stoffel-
nificant reduction of seizure frequency in women Wagner et al., 2000). The progesterone metabolite
with medically intractable focal epilepsy and cata- 3a,5a THP seems to be a more potent anticonvul-
menial seizure exacerbation (Herzog, 1986, 1995, sant agent than progesterone itself (Landgren et
1999a). The cyclic variation of serum steroid hor- al., 1987; Frye, 1995; Kokate et al., 1999) and
mones can also be suppressed by the administra- inhibits convulsions induced by picrotoxin (Bäck-
tion of synthetic analogues of the gonadotrophic ström et al., 1990). Among the 5a-reduced
releasing hormone (GnRH). Bauer et al. (1992) metabolites of progesterone, 3a,5a THP is the
used triptorelin, a synthetic GnRH agonist, as most potent positive-allosteric modulator of the
add-on treatment in ten women with catamenial GABAA receptor complex (Lephart, 1993). Con-
seizures. As a result of this therapy, three of ten sequently, these compounds may have an influ-
women became seizure free and in another five ence on the functions of cerebral neurons,
women, seizure frequency decreased or seizures especially in epileptic foci. In general, naturally
were less severe. The effect of GnRH analogues occurring 3a-reduced neuroactive steroids exert
on catamenial seizures was also demonstrated by anticonvulsant effects (Belelli et al., 1990; Kokate
other investigators (Haider and Barnett, 1991; et al., 1994, 1998, 1999).
Reid and Gangar, 1992). Since GnRH analogues Estrogen, by contrast, lowers the seizure
do suppress the release of ovarian hormones, a threshold. It potentiates glutamate and blocks
therapeutic effect can only be expected in women GABA-mediated neurotransmission (Smith et al.,
with ovulatory cycles (Bauer et al., 1995, 1998). 1988; Smith, 1989; Murphy et al., 1998; Woolley
Long term administration of synthetic GnRH and Schwartzkroin, 1998; Woolley, 1999). When
analogues (agonists as well as antagonists) is lim- applied to hippocampal neurons, estrogen poten-
ited by the risk of severe adverse events, e.g. bone tiates the postsynaptic response to synaptically
demineralisation (Waibel-Treber et al., 1989). In released glutamate or exogenous kainate (Wool-
patients with anovulatory cycles, supplementation ley, 1999). There is evidence that the effects of
of progesterone during the second half of the estradiol on seizure susceptibility may not result
cycle or the conversion to ovulatory cycles (using from increased neuronal excitability throughout
clomiphene) may reduce seizure frequency signifi- the brain. Estradiol predominantly acts on neu-
cantly (Herzog, 1988, 1999a). Furthermore, the rons within the limbic system (Woolley, 2000). In
premenstrual syndrome, which is characterized by female rats, estradiol lowers limbic afterdischarge
symptoms such as depression, anxiety and suscep- thresholds and facilitates kindling, whereas
tibility to seizures, appears to be related to low- progesterone exerts the opposite effects (Edwards
ered circulating levels of progesterone (Britton et al., 1999a). Genomic effects of estrogen in-
and Koob, 1998). Thus, fluctuations in the con- cludes the alteration of the mRNA that encodes
centration of neurosteroids could at least in part for GABA amino decarboxylase (GAD). Estrogen
be responsible for mood swings and increased also reduces the rate of synthesis of GABAA
vulnerability to developing seizures and migraine receptor subunits (Woolley and Schwartzkroin,
during the perimenstrual phase. 1998; Morrell, 1999; Woolley, 1999). The estra-
These clinical findings are supplemented by nu- diol-induced down-regulation of GAD and its
merous animal studies. Their results have been product, GABA, and the subsequent reduction of
summarized recently (Joels, 1997; Bäckström and miniature inhibitory postsynaptic currents in both
Rosciszewska, 1997; Herzog, 1999b): progesterone size and frequency in hippocampal neurons indi-
exerts anticonvulsive effects in acute and chronic cate that estradiol decreases GABAergic inhibi-
epilepsy models (Joels, 1997; Bäckström and tion in the hippocampus. Thus, estradiol causes
Rosciszewska, 1997; Herzog, 1999b). Proges- an increase in the excitatory drive on pyramidal
terone may be converted into highly neuroactive neurons in the hippocampus and leads to the
compounds, in particular allopregnanolone formation of new dendritic spines (Murphy and
(3a,5a-tetrahydroprogesterone, 3a,5a THP) (Lep- Segal, 1996; Murphy et al., 1998). Progesterone,
S. Beyenburg et al. / Epilepsy Research 44 (2001) 141–153 145

via conversion to THP, blocks the effects of estra- 2000b). Interestingly, there is evidence that the
diol on dendritic spines (Murphy and Segal, 2000). human hippocampus is an important target for
As estradiol increases the number of dendritic neurosteroidal actions, since this brain region is
spines and axospinous synapses on hippocampal equipped with enzymes that are necessary for sex
pyramidal cells, it has been suggested that these steroid formation and metabolism (Beyenburg et
structural and functional changes in hippocampal al., 1999, 2000a; Stoffel-Wagner et al., 2000): Cy-
circuitry may contribute to increased susceptibility tochrome P450scc induces de novo synthesis of
to limbic seizure activity (Woolley and McEwen, neurosteroids. It is the single enzyme mediating
1993; Woolley et al., 1996; Woolley, 1999, 2000). the conversion of the steroid precursor, choles-
The effects of androgens on neuronal excitabil- terol, to pregnenolone. The human hippocampus
ity have not been investigated extensively. Andro- and other human brain regions have the enzy-
gens raise the seizure threshold in some matic capability to convert cholesterol into preg-
experimental models of epilepsy (Bäckström and nenolone (Beyenburg et al., 1999; Watzka et al.,
Rosciszewska, 1997). There is some evidence that 1999). Once pregnenolone is produced from
testosterone, the principal circulating androgen cholesterol, it may be converted to progesterone
and its 5a-reduced metabolite 5a-androstane-3a, and other neuroactive steroids (Mensah-Nyagan
17b-diol (3a-diol), do exert anticonvulsant effects, et al., 1999). Moreover, mRNA of 5a-reductase
probably via interaction with GABAA/benzodi- and 3a-hydroxisteroid oxidoreductase is expressed
azepine receptor complexes (Schwartz-Giblin et within the human hippocampus. These enzymes
al., 1989; Thomas and McLean, 1991; Frye and are necessary for the major neuroendocrine con-
Reed, 1998). However, it was demonstrated that
version of progesterone via 5a-reduction and 3a-
testosterone and its metabolites, estradiol and 5a-
hydroxisteroid oxidoreduction leading to the
dihydrotestosterone (DHT), do exert epilepto-
potent neurosteroid allopregnanolone (3a,5a-
genic effects in male rats (Edwards et al., 1999b).
THP) (Stoffel-Wagner et al., 2000). In addition,
Estradiol may potentiate glutamate neurotrans-
the activity of these enzymes has been demon-
mission (Smith et al., 1988). Thus, the effect of
strated in the human temporal lobe (Stoffel-Wag-
testosterone on neuronal excitability is controver-
ner et al., 1998a; Steckelbroeck et al., 1999b).
sial and also depends on the balance of its conver-
sion to DHT and estradiol. Testosterone therapy Several isozymes of 17b-hydroxisteroid dehydro-
in epilepsy seems to improve seizure control if genases (17b-HSDs), which play a pivotal role in
used with an aromatase inhibitor, which inhibits catalyzing the final steps of androgen and estrogen
the conversion of androgen to estrogen (Herzog et biosynthesis (Mensah-Nyagan et al., 1999), are
al., 1998). expressed in epileptic human hippocampus
The findings described above provide evidence (Beyenburg et al., 2000a). Androgenic and estro-
for a role of neuroactive steroid hormones in the genic 17b-HSD activities are also present in the
occurrence of epileptic seizures. One of the most human temporal lobe in patients with epilepsy
vulnerable brain regions is the hippocampal for- (Steckelbroeck et al., 1999b). Furthermore, cy-
mation. Similar to other temporolimbic structures, tochrome P450 aromatase, the product of the
the hippocampus displays low thresholds for CYP19 gene which catalyses the conversion of
seizure induction (Schwartzkroin and McIntyre, androgens to estrogens, is expressed in the human
1997; Woolley and Schwartzkroin, 1998). Limbic hippocampus and temporal lobe (Stoffel-Wagner
structures show sensitive electrophysiological re- et al., 1999b) and its enzyme activity has been
sponses to steroid hormone exposure (Joels, 1997). characterized in the human temporal lobe (Steck-
High concentrations of glutamate and GABA re- elbroeck et al., 1999a). These investigations of the
ceptors, as well as densely distributed sex steroid expression and activity of steroidogenic enzymes
hormone receptors, have been described within in the human brain (Stoffel-Wagner et al.,
this specific brain region (Tohgi et al., 1995; Her- 1998a,b, 1999a, 2000; Steckelbroeck et al.,
zog, 1999b; Morrell, 1999; Beyenburg et al., 1999a,b; Beyenburg et al., 1999, 2000a), as
146 S. Beyenburg et al. / Epilepsy Research 44 (2001) 141–153

well as post mortem studies on the distribution of the anesthetic and sedative properties of proges-
neuroactive steroids in different regions of the terone and some of its metabolites (Selye, 1941).
human brain (Hammond et al., 1983; Lanthier These substances exert their effects rapidly and
and Patwardhan, 1986; Lacroix et al., 1987; Bixo today it is well established that the underlying
et al., 1997) indicate that neurosteroidogenesis mechanisms of these properties are unrelated to
occurs in human limbic structures and other parts the ‘classic’ endocrine effects of such hormones
of the human brain. (Paul and Purdy, 1992; Majewska, 1992; Mellon,
In humans, studies proving epilepsy-related al- 1994; Rupprecht and Holsboer, 1999a,b). In other
terations of neurosteroidogenic enzymes or neu- words, in contrast to the classic actions of steroid
roactive compounds are still missing. Since recent hormones, which regulate gene transcription via
studies indicate seizure associated changes in the interactions with intracellular steroid receptors,
expression pattern of different GABAA receptor neuroactive steroids exert actions on the brain by
subunits (Brooks-Kayal et al., 1998; Shumate et altering the excitability of membrane-bound re-
al., 1998) or GABA transporters (During et al., ceptors. The mechanism of action of such steroids
1995), pathophysiological consequences of puta- resembles that of neurotransmitters. Neuroactive
tively altered expression levels of neuros- steroids and their A-ring reduced metabolites in-
teroidogenic enzymes on human epilepsy related duce rapid effects on neuronal excitability possi-
differences in GABAA receptor or other receptor bly by allosteric interaction with a putative steroid
expression profiles have to be analyzed. recognition site on the g-aminobutyric acidA
(GABAA) receptor–ion–channel complex. This
2.2. Corticosteroids binding leads to either inhibition or potentiation
of the inhibitory effects of GABA. Inhibition of
Adrenal steroid hormones may act as neuroac- GABA-receptor function produces effects ranging
tive substances. A certain relationship between from anxiety and excitability to seizure suscepti-
corticosteroid and seizures has been described bility, while potentiation of GABA-ergic effects
(Heuser and Eidelberg, 1961; Herzog, 1991). Min- produces anticonvulsant and anxiolytic effects,
eralocorticoids and glucocorticoids alter neuronal sedation and sleep (Paul and Purdy, 1992; Lam-
excitability (Joels and de Kloet, 1990; Joels, 1997; bert et al., 1995; Joels, 1997; Rupprecht and Hols-
Bäckström and Rosciszewska, 1997; Joels and boer, 1999a,b). For example, anticonvulsive,
Vreugdenhil, 1998) and mRNA expression of anesthetic and anxiolytic effects of neuroactive
their respective receptors has been demonstrated compounds, including 3a,5a THP, are mediated
in the hippocampus (Tohgi et al., 1995; Watzka et by the capacity of 3a,5a THP to positively modu-
al., 2000a) as well as in other parts of the brain of late GABAA receptor function, i.e. these sub-
patients with epilepsy (Watzka et al., 2000b). stances act to increase GABA-ergic effects by
From both acute and chronic models for epilepsy increasing the frequency and duration of chloride
there is evidence that high corticosterone levels channel openings (Majewska et al., 1986; Majew-
may exacerbate seizure occurrence (Kling et al., ska, 1992; Paul and Purdy, 1992; Mellon, 1994).
1993; Roberts and Keith, 1995; Karst et al., There is evidence of a putative specific steroid-
1999). binding site at the GABAA-receptor (Paul and
Purdy, 1992; Lambert et al., 1995; Rupprecht and
Holsboer, 1999a).
3. Actions and effects of neuroactive steroids in Additionally, other actions of neuroactive
the central nervous system steroids have been described, including the inhibi-
tion of voltage-gated Ca2 + currents and the mod-
The major effects of neuroactive steroids on ulation of N-methyl-D-aspartate (NMDA),
seizure susceptibility are mediated through their nicotinic, muscarinic, 5-HT3, AMPA, kainate,
direct or modulatory action on ligand or voltage- glycine and sigma receptors (Lambert et al., 1995;
gated ion channels. In 1941, Hans Selye described Rupprecht and Holsboer, 1999a; Mensah-Nyagan
S. Beyenburg et al. / Epilepsy Research 44 (2001) 141–153 147

et al., 1999; Zinder and Dar, 1999). To what thaler, 2000; Koenig, 2001). However, steroid re-
extent these other modulatory actions contribute ceptor-mediated gene regulation may, at least
to alterations in seizure susceptibility remains to partly, be involved in the hormone-dependent
be elucidated. Some neuroactive steroids enhance changes in seizure susceptibility (Morrell, 1992,
the effects of amino acid neurotransmitters, i.e. 1999; Joels, 1997; Herzog, 1999b). The main
glutamate and glycine, thus contributing to an mechanisms of action and the prominent effects
elevation of neuronal excitability (Rupprecht and on neuronal excitability of neuroactive sex
Holsboer, 1999a; Zinder and Dar, 1999). How- steroids are summarized in Table 1.
ever, other steroids protect aginst NMDA-in- In conclusion, neuroactive steroids regulate
duced seizures (Gasior et al., 1997; Herzog, neuronal function via their concurrent influence
1999b). The anti-NMDA action of neuroactive on gene expression and transmitter-gated ion
steroids might be clinically important, since channels. Whether genomic or nongenomic effects
NMDA-induced excitation is involved in seizure of these compounds predominate in the target
susceptibility (Chapman, 2000). It has been sug- tissues mainly depends on the expression patterns
gested that some neuroactive steroids modulate of steroid receptors, GABAA receptors and of the
the NMDA response via sigma receptors enzymes that are present in situ (Rupprecht and
(Bergeron et al., 1996). Moreover, as some neu- Holsboer, 1999b). These actions suggest that neu-
roactive steroids inhibit voltage-gated Ca2 + chan- roactive steroids play a crucial role in mediating
nels and enhanced neuronal influx of Ca2 + ions various brain functions. They may have effects on
plays a pivotal role in the initiation and spread of declarative memory processes (McEwen et al.,
seizure activity, this inhibitory action on voltage- 1997; Schumacher et al., 1997), the stress response
gated Ca2 + channels may contribute to anticon- (Zinder and Dar, 1999) and seizure susceptibility
vulsant effects of such compounds (Gasior et al., (Bäckström and Rosciszewska, 1997; Joels, 1997;
1997). Furthermore, it has been postulated that Herzog 1999b,c). Steroid compounds may also
neuroactive steroids act on nerve cells through play a role in the development of other physiolog-
proper membrane receptors coupled to G proteins ical phenomena such as emotional behaviour (i.e.
(Orchinik et al., 1992) and may interact with aggression and anxiety), sedation and sleep and,
various neuropeptide receptors (Grazzini et al., as a consequence, their aberrant synthesis or
1998) contributing to G-protein-related signal metabolism may form a basis for diseases such as
transduction. In addition, other steroid effects migraine, depression, the premenstrual syndrome
have emerged, e.g. estrogen may serve as a neuro- and epilepsy (Majewska, 1992; Mellon, 1994;
protective antioxidant (Behl and Holsboer, 1999). Mensah-Nyagan et al., 1999; Zinder and Dar,
Finally, there is evidence that neuroactive steroids 1999). In addition, neuroactive steroids promote
may regulate gene expression by activating neuronal and glial growth and neuronal synaptic
progesterone receptors (Rupprecht et al., 1993; contact by regulating gene expression (Tsutsui et
Rupprecht and Holsboer, 1999a,b). In the postpu- al., 2000).
bertal brain, estrogen, progesterone and androgen
receptors are predominantly concentrated in hy-
pothalamic and limbic regions. Corticosteroid re- 4. Therapeutical considerations
ceptors are located mainly in limbic areas, such as
the hippocampal formation, the paraventricular Since progesterone and 3a-reduced pregnane
nucleus of the hypothalamus and in certain mid- steroids have potent anticonvulsant effects, at-
brain structures. The impact of steroid receptor tempts to develop novel antiepileptic drugs with
localization in the hippocampus and cerebral cor- neurosteroidal properties seem reasonable. In pre-
tex on brain functions has been reviewed else- clinical studies, metabolites of progesterone and
where (Morrell, 1992, 1999; McEwen et al., 1997; deoxycorticosterone, as well as the synthetic neu-
Joels and Vreugdenhil, 1998; Kawata et al., 1998; roactive steroid ganaxolone, exhibit a broad anti-
Schumacher et al., 1999; Shughrue and Merchen- convulsant profile in different animal models (for
148
Table 1
Mechanisms of action and effects on neuronal excitability of sex steroids (modified from Herzog, 1999b; Rupprecht and Holsboer, 1999a; Morrell, 1999)

S. Beyenburg et al. / Epilepsy Research 44 (2001) 141–153


Estradiol Progesterone Testosterone

Specific receptor Primarily hypothalamic and limbic Primarily hypothalamic and limbic Primarily hypothalamic and limbic
sites
CNS-active Catechol estrogens Allopregnanolone Estradiol, dihydrotestosterone, androstandiol
metabolites
Membrane GABA, NMDA, kainate, 5-HT3 GABA, NMDA, nicotinic acetylcholine, GABA, NMDA, 5-HT3
receptor glycine, 5-HT3, kainate, oxitocin, sigma I
modulation
Effects on Inhibits GABA synthesis. Reduces numbers Increases GABA synthesis. Increases numbers Controversial, may exert pro- and
neuronal of GABAA receptor subunits. Induces of GABAA receptor subunits. Counteracts the anticonvulsant effects.
excitability formation of new dendritic spines. effects of estradiol on dendritic spine density.
Reduces electroconvulsive shock threshold. Increases electroconvulsive shock threshold.
Creates new seizure focus when applied Suppresses seizures induced by kindling, focal
topically to the cortex. Increases severity and lesions and alcohol withdrawal. Increases
duration of chemically induced seizures. threshold for seizures induced by chemical
Activates preexisting epileptogenic foci. convulsants. Induces sedation and anesthesia.
S. Beyenburg et al. / Epilepsy Research 44 (2001) 141–153 149

review see Gasior et al., 1999). Ganaxolone is a patients) were generally mild and included somno-
member of a novel class of neuroactive steroids, lence, diarrhoea, nervousness and vomiting. The
called epalons, which allosterically modulate the tolerability of ganaxolone at doses up to 36 mg/kg
GABAA receptor complex. Ganaxolone is chemi- per day was acceptable. Ganaxolone monother-
cally related to progesterone, but is devoid of apy was evaluated in a recent randomized, dou-
hormonal activity (Gee et al., 1995; Carter et al., ble-blind, presurgical clinical trial. Ganaxolone
1997; Gasior et al., 1999). The steroid has been was administered at a dose of 1500 mg per day on
shown to be an efficacious anticonvulsive com- day 1 and 1875 mg per day on days 2–8. The
pound in a variety of acute seizure models, as well tolerability of ganaxolone was similar to that of
as in electrical and chemical kindling models placebo and the drug showed significant
(Gasior et al., 1999, 2000; Liptakova et al., 2000; antiepileptic activity, which was measured by the
Reddy and Rogawski, 2000a,b). In animal studies, duration of treatment before withdrawl from the
there seems to be no tolerance to the anticonvul-
study (Laxer et al., 2000). Thus, limited experi-
sant activity of ganaxolone when administered
ence from clinical studies suggests that ganax-
chronically over the course of up to 7 days.
olone is effective and well tolerated, the
Ganaxolone induced cross-tolerance to the anti-
dose-limiting side-effect is sedation due its
convulsant activity of diazepam, that was com-
parable in magnitude to that produced by chronic GABAergic action. However, one has to keep in
diazepam treatment itself (Reddy and Rogawski, mind that neuroactive steroids also affect other
2000b). In addition, it has also been demonstrated neurotransmitter receptors and gene expression
that anticonvulsant tolerance does not develop to (Rupprecht and Holsboer, 1999a,b), which could
pregnanolone with intermittent chronic dosing contribute to their clinical efficacy as well as to
(Kokate et al., 1998). Similarly, tolerance has not their side-effect profiles. The anticonvulsant activ-
been observed to the anxiolytic and sedative ef- ity of these compounds has been mainly at-
fects of other synthetic neuroactive steroids, e.g. tributed to their GABAA-enhancing action, but
alphaxolone and 3b-ethenyl-3a-hydroxy-5a-preg- may also be related to combined actions on
nan-20-one (Green et al., 1978; Wieland et al., GABA and NMDA receptors or voltage-gated
1997), whereas tolerance development to the Ca2 + channels (Gasior et al., 1997).
steroid minaxolone has been reported (Marshall In summary, neuroactive steroids are involved
et al., 1997). These findings suggest that some, but in the regulation of many (physiological) brain
not all, neuroactive steroids may have a lower functions, such as anxiety, aggressive behavior,
propensity for tolerance than benzodiazepines. sleep, stress responses and cognitive functions.
In humans, ganaxolone showed a promising They may be involved in the manifestation of
pharmacokinetic profile and was well tolerated in diseases characterized by alterations of cerebral
a trial with 96 healthy volunteers (Monaghan et excitability, such as epilepsy and others. However,
al., 1997a). The steroid proved to be well tolerated the amount of their impact on diseases still re-
(Monaghan et al., 1997b) and effective in clinical mains to be elucidated. Neuropharmacological
studies with epilepsy patients (Shields et al., 1997; properties of neuroactive steroids, e.g. anticonvul-
Kerrigan et al., 2000; Laxer et al., 2000). In six of sant, antidepressant, anesthetic, memory enhanc-
15 children with medically refractory seizures and ing and other effects, point to a future role for
a history of infantile spasms, adjunctive ganax-
these compounds in clinical practice.
olone therapy resulted in a mean decrease in
spasm frequency of \50% (Shields et al., 1997).
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