Neuroactive steroids and seizure susceptibility
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
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