Neuroactive steroids and seizure susceptibility

https://doi.org/10.1016/S0920-1211(01)00194-2Get rights and content

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 progesterone 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.

Introduction

Hormones, particularly sex steroid hormones, influence the probability of seizure occurrence. From a clinical point of view, the development of certain epilepsy syndromes — such as absence epilepsy or juvenile myoclonic epilepsy — temporally corresponds to alterations in hormonal balance during puberty. In women, changes in hormones during the menstrual cycle, at puberty, during pregnancy and menopause may influence seizure frequency (Morrell, 1992, Morrell, 1999, Herzog, 1999b, Herzog, 1999c). However, the mechanisms by which steroid hormones modulate seizure vulnerability are not yet fully understood.

Steroid hormones are mainly synthesized in the adrenal glands (mineralo- and glucocorticoids), gonads and the fetoplacental unit (sex hormones, i.e. androgens, estrogens and progesterone). Due to their high lipid solubility, they cross the blood–brain barrier easily. The brain is regarded as a target for steroid actions because these hormones can affect neuroendocrine and behavioral brain functions via binding to cytosolic intracellular receptors, thus activating the genome for transcription and protein synthesis. The response to these steroid actions is observed with a delay of hours to days (delayed, genomic actions) (Majewska, 1992, Mellon, 1994, Lambert et al., 1995, Joels, 1997, Rupprecht and Holsboer, 1999a, Rupprecht and Holsboer, 1999b). Apart from these actions, certain steroids and their metabolites alter neuronal excitability within seconds to minutes (fast, nongenomic actions). The mechanism of this action is a modulation of the activity of a variety of neurotransmitter receptors and ion channels on the cell surface, e.g. γ-aminobutyric acidA (GABAA) and N-methyl-d-aspartate (NMDA) receptors (Majewska, 1992, Mellon, 1994, Lambert et al., 1995, Joels, 1997, Rupprecht and Holsboer, 1999a, Rupprecht and Holsboer, 1999b). For steroids with these properties, the term ‘neuroactive steroids’ has been coined (Paul and Purdy, 1992, Majewska, 1992, Mellon, 1994). Moreover, the brain is not only a target tissue for actions of neuroactive steroids from peripheral sources, but may also produce steroids de novo from cholesterol. Such steroids have been defined as neurosteroids and include compounds such as dehydroepiandrosterone (DHEA) and pregnenolone, as well as their esters (DHEA sulfate and pregnenolone sulfate, respectively), progesterone and the 5α-reduced progesterone metabolite, allopregnanolone (3α-OH-5α-pregnan-20-one, 3α,5α-tetrahydroprogesterone) (Baulieu, 1998, Mensah-Nyagan et al., 1999). In the brains of vertebrates, glial cells are the major site for neurosteroid formation and metabolism (Baulieu, 1998). Recent studies demonstrated that these substances may also be synthesized by neurons (Tsutsui et al., 2000).

The present review focuses on the effects of neuroactive steroids on neuronal excitability and their putative impact on the physiology of epileptic disorders. Details of biosynthesis and metabolism of neuroactive steroids have been reviewed previously (Paul and Purdy, 1992, Majewska, 1992, Mellon, 1994, Baulieu, 1998, Mensah-Nyagan et al., 1999). Furthermore, recent findings on the mRNA expression of neurosteroidogenic enzymes in the brains of patients with epilepsy are summarized. Fig. 1 shows important steps of neurosteroid biosynthesis.

Section snippets

Sex hormones

Several lines of evidence suggest that neuroactive steroids modulate seizure susceptibility. Early observations described the impact of estrogens on the exacerbation of seizures in women with epilepsy (Logothetis et al., 1959). Subsequent experimental studies confirmed the proconvulsant effects of estrogens (Logothetis and Harner, 1960, Stitt and Kinnard, 1968). From a clinical point of view, the influence of sex hormones on the occurrence of epileptic seizures is best documented in female

Actions and effects of neuroactive steroids in the central nervous system

The major effects of neuroactive steroids on seizure susceptibility are mediated through their direct or modulatory action on ligand or voltage-gated ion channels. In 1941, Hans Selye described the anesthetic and sedative properties of progesterone and some of its metabolites (Selye, 1941). These substances exert their effects rapidly and today it is well established that the underlying mechanisms of these properties are unrelated to the ‘classic’ endocrine effects of such hormones (Paul and

Therapeutical considerations

Since progesterone and 3α-reduced pregnane steroids have potent anticonvulsant effects, attempts to develop novel antiepileptic drugs with neurosteroidal properties seem reasonable. In preclinical studies, metabolites of progesterone and deoxycorticosterone, as well as the synthetic neuroactive steroid ganaxolone, exhibit a broad anticonvulsant profile in different animal models (for review see Gasior et al., 1999). Ganaxolone is a member of a novel class of neuroactive steroids, called

References (119)

  • M. Gasior et al.

    Neuroactive steroids: potential therapeutic use in neurological and psychiatric disorders

    Trends Pharmacol. Sci.

    (1999)
  • M. Gasior et al.

    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)
  • Y. Haider et al.

    Catamenial epilepsy and gosorelin (letter)

    Lancet

    (1991)
  • G.L. Hammond et al.

    Progesterone, androstene-dione, testosterone, 5α-dihydrotestosterone and androsterone concentrations in specific regions of the human brain

    J. Ster. Biochem.

    (1983)
  • G.K. Herkes et al.

    Patterns of seizure occurrence in catamenial epilepsy

    Epilepsy Res.

    (1993)
  • A.G. Herzog

    Psychoneuroendocrine aspects of temporolimbic epilepsy. Part I. Brain, reproductive steroids, and emotions

    Psychosomatics

    (1999)
  • A.G. Herzog

    Psychoneuroendocrine aspects of temporolimbic epilepsy. Part II. Epilepsy and reproductive steroids

    Psychosomatics

    (1999)
  • M. Joels

    Steroid hormones and excitability in the mammalian brain

    Front. Neuroendocrinol.

    (1997)
  • M. Kawata et al.

    Steroid hormones and their receptors in the brain

    J. Ster. Biochem. Mol. Biol.

    (1998)
  • J.F. Kerrigan et al.

    Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial

    Epilepsy Res.

    (2000)
  • M.A. Kling et al.

    Facilitation of cocaine kindling by glucocorticoids in rats

    Brain Res.

    (1993)
  • J.I. Koenig

    Estrogen and brain function

    Trends Endocrinol. Metab.

    (2001)
  • C. Lacroix et al.

    Simultaneous radioimmunoassay of progesterone, androst-4-enedione, pregnenolone, dehydroepiandrosterone and 17-hydroxyprogesterone in specific regions of human brain

    J. Ster. Biochem.

    (1987)
  • J.J. Lambert et al.

    Neurosteroids and GABAA receptor function

    Trends Pharmacol. Sci.

    (1995)
  • A. Lanthier et al.

    Sex steroids and 5-en-3β-hydroxysteroids in specific regions of human brain and cranial nerves

    J. Ster. Biochem.

    (1986)
  • E.D. Lephart

    Brain 5α-reductase: Cellular, enzymatic, and molecular perspectives and implications for biological function

    Mol. Cell. Neurosci.

    (1993)
  • F.H. Marshall et al.

    Development of tolerance in mice to the sedative effects of the neuroactive steroid minaxolone following chronic exposure

    Pharmacol. Biochem. Behav.

    (1997)
  • B.A. Reid et al.

    Catamenial epilepsy and gosorelin (letter)

    Lancet

    (1992)
  • A.J. Roberts et al.

    Corticosteroids enhance convulsion susceptibility via central mineralocorticoid receptors

    Psychoneuroendocrinology

    (1995)
  • R. Rupprecht et al.

    Neuroactive steroids: mechanism of action and neuropsychopharmacological perspectives

    Trends Neurosci.

    (1999)
  • R. Rupprecht et al.

    Progesterone receptor-mediated effects of neuroactive steroids

    Neuron

    (1993)
  • M. Schumacher et al.

    Genomic and membrane actions of progesterone: implications for reproductive physiology and behaviour

    Behav. Brain Res.

    (1999)
  • S. Schwartz-Giblin et al.

    Steroid hormone effects on picrotoxin-induced seizures in female and male rats

    Brain Res.

    (1989)
  • P.J. Shughrue et al.

    Estrogen is more than just a ‘sex hormone’: Novel sites for estrogen action in the hippocampus and cerebral cortex

    Front. Neuroendocrinol.

    (2000)
  • M.D. Shumate et al.

    GABA(A) receptor function in epileptic human dentate granule cells: comparison to epileptic and control rat

    Epilepsy Res.

    (1998)
  • S.S. Smith

    Estradiol administration increases neuronal responses to excitatory amino acids as a long term effect

    Brain Res.

    (1989)
  • S.S. Smith et al.

    Locally applied estrogens potentiate glutamate-evoked excitation of cerebellar Purkinje cells

    Brain Res.

    (1988)
  • T. Bäckström et al.

    Effects of hormones on seizure expression

  • T. Bäckström et al.

    Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy

    Acta Neurol. Scand.

    (1984)
  • T. Bäckström et al.

    Steroids in relationship to epilepsy and anaesthesia

  • J. Bauer et al.

    The effect of a synthetic GnRH analogue on catamenial epilepsy: a study in ten patients

    J. Neurol.

    (1992)
  • J. Bauer et al.

    Catamenial seizures: an analysis (in German)

    Nervenarzt

    (1995)
  • J. Bauer et al.

    Seizure occurrence during ovulatory and anovulatory cycles in patients with temporal lobe epilepsy: a prospective study

    Eur. J. Neurol.

    (1998)
  • R. Bergeron et al.

    Potentiation of neuronal NMDA response induced by dehydroepiandrosterone and its suppression by progesterone: effects mediated via sigma receptors

    J. Neurosci.

    (1996)
  • S. Beyenburg et al.

    Expression of cytochrome P450scc mRNA in the hippocampus of patients with temporal lobe epilepsy

    NeuroReport

    (1999)
  • K.T. Britton et al.

    Premenstrual steroids?

    Nature

    (1998)
  • A.R. Brooks-Kayal et al.

    Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy

    Nat. Med.

    (1998)
  • R.B. Carter et al.

    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)
  • A.G. Chapman

    Glutamate and epilepsy

    J. Nutr.

    (2000)
  • S. Duncan et al.

    How common is catamenial epilepsy?

    Epilepsia

    (1993)
  • Cited by (98)

    • The intersections of stress, anxiety and epilepsy

      2020, International Review of Neurobiology
    • Epileptogenic effects of G protein-coupled estrogen receptor 1 in the rat pentylenetetrazole kindling model of epilepsy

      2016, Pharmacological Reports
      Citation Excerpt :

      GPER1 receptor agonist G-1 can increase epileptogenic effects via changing cortex and hippocampus oxidative or antioxidative parameters. The stimulatory and epileptogenic properties of estrogens and their role in the epilepsy are well established elsewhere [29–31]. Also, rapid stimulatory effects of 17β-estradiol on kindled seizure parameters have been demonstrated previously in male rats [32,33].

    View all citing articles on Scopus
    View full text