Elsevier

Neurobiology of Disease

Volume 72, Part B, December 2014, Pages 198-209
Neurobiology of Disease

Review
Neurosteroids and their role in sex-specific epilepsies

https://doi.org/10.1016/j.nbd.2014.06.010Get rights and content

Highlights

  • This article describes the role of neurosteroids in sex-specific epilepsies.

  • Neurosteroids are anticonvulsants and also exert antiepileptogenic effects.

  • Neurosteroids such as allopregnanolone play a key role in catamenial epilepsy.

  • Alterations of GABA receptor plasticity & function are evident in epilepsy models.

  • Neurosteroid replacement therapy is useful for sex-specific forms of epilepsies.

Abstract

Neurosteroids are involved in sex-specific epilepsies. Allopregnanolone and related endogenous neurosteroids in the brain control excessive neuronal excitability and seizure susceptibility. Neurosteroids activate GABA-A receptors, especially extrasynaptic αγδ-GABA-A receptor subtypes that mediate tonic inhibition and thus dampen network excitability. Our studies over the past decade have shown that neurosteroids are broad-spectrum anticonvulsants and confer seizure protection in various animal models. Neurosteroids also exert antiepileptogenic effects. There is emerging evidence on a critical role for neurosteroids in the pathophysiology of the sex-specific forms of epilepsies such as catamenial epilepsy, a menstrual cycle-related seizure disorder in women. Catamenial epilepsy is a neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around the perimenstrual or periovulatory period. Apart from ovarian hormones, fluctuations in neurosteroid levels could play a critical role in this gender-specific epilepsy. Neurosteroids also regulate the plasticity of synaptic and extrasynaptic GABA-A receptors in the hippocampus and other regions involved in epilepsy pathology. Based on these studies, we proposed a neurosteroid replacement therapy for catamenial epilepsy. Thus, neurosteroids are novel drug targets for pharmacotherapy of epilepsy.

Introduction

Neurosteroids are steroids synthesized within the brain with unconventional, rapid effects on neuronal excitability. Neurosteroids and their precursor steroid hormones play an important role in the neuronal excitability, seizure susceptibility, and pathophysiology of epilepsy. The term neurosteroid refers to steroids that are synthesized de novo in the nervous system from cholesterol, independent of the peripheral steroidogenic endocrine glands (Baulieu, 1981). 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 can exert anesthetic and anticonvulsant actions (Clarke et al., 1973, Selye, 1941, Selye, 1942). In the early 1980s, the synthetic steroid alphaxolone was found to enhance synaptic inhibition via an action on GABA-A receptors in the brain (Harrison and Simmonds, 1984). A major advance occurred when 5α-reduced metabolites of progesterone and deoxycorticosterone were also found to enhance GABA-A receptor function (Majewska et al., 1986). Consequently, it became evident that the anticonvulsant properties of progesterone and deoxycorticosterone are predominantly due to their conversion in the brain to the neurosteroids allopregnanolone (3α-hydroxy-5α-pregnane-20-one, AP) and allotetrahydro-deoxycorticosterone (3α,21-dihydroxy-5α-pregnan-20-one; THDOC), respectively (Carver and Reddy, 2013, Reddy, 2003, Reddy, 2004a, Reddy, 2004b, Reddy, 2011a, Reddy, 2011b) (Fig. 1). This article describes the neurobiological aspects of neurosteroids with a special emphasis on catamenial epilepsy, a menstrual cycle-related seizure disorder in women. It focuses on the role of GABA-A receptor-modulating neurosteroids in regulating both seizure susceptibility and pathophysiology of sex-specific epilepsies.

Section snippets

Neurosteroid biosynthesis in the brain

A variety of neurosteroids are synthesized in the brain (Baulieu, 1981, Kulkarni and Reddy, 1995). The most widely studied are allopregnanolone, THDOC, and androstanediol (Fig. 1). There is now compelling evidence that all of the enzymes required for the biosynthesis of the neurosteroids from cholesterol are present in the brain (Stoffel-Wagner et al., 2000, Stoffel-Wagner et al., 2003). Allopregnanolone and related neurosteroids are produced via sequential A-ring reduction of the steroid

Neurosteroid activation of GABA-A receptors

Neurosteroids rapidly alter neuronal excitability through direct interaction with GABA-A receptors (Carver and Reddy, 2013, Gee et al., 1988; Harrison and Simmonds 1984, Harrison et al., 1987, Hosie et al., 2007, Hosie et al., 2009, Majewska et al., 1986). Activation of the GABA-A receptor by various ligands leads to an influx of chloride ions and to a hyperpolarization of the membrane that dampens the excitability. Allopregnanolone, THDOC and other structurally-related neurosteroids act as

Anticonvulsant and antiepileptogenic activity of neurosteroids

Allopregnanolone and related neurosteroids are powerful anticonvulsants. Neurosteroids exhibit broad-spectrum anticonvulsant effects in diverse rodent seizure models (Reddy, 2010, Reddy, 2011a, Reddy, 2011b). Neurosteroids protect against seizures induced by GABA-A receptor antagonists, including pentylenetetrazol and bicuculline, and are effective against pilocarpine-induced limbic seizures and seizures in kindled animals (Belelli et al., 1989, Frye, 1995, Kokate et al., 1994, Reddy et al.,

Role of neurosteroids in sex-specific forms of epilepsy

Sex difference in seizure susceptibility is one of the long-standing issues of epilepsy. Clinical evidence shows gender- and age-related expression in many seizure syndromes. The incidence of epilepsy is generally higher in males than in females (Christensen et al., 2005, Hauser, 1997). More women than men are diagnosed with idiopathic generalized epilepsy, but localization-related symptomatic epilepsies are more frequent in men, and cryptogenic localization-related epilepsies are more frequent

Catamenial epilepsy

Epilepsy is characterized by the unpredictable occurrence of seizures. However, seizures do not occur randomly in many women with epilepsy. Seizure clusters occur with a temporal periodicity following circadian or lunar cycles. In women with epilepsy, seizure periodicity may conform to the menstrual cycle according to a “menstrual clock” provided by a common phase marker of the onset of menses (Gowers, 1881). Catamenial epilepsy, derived from the Greek word kataminios, meaning “monthly”, is

Neuroendocrine mechanisms of catamenial epilepsy

Catamenial epilepsy is a multifaceted condition attributed to numerous causes. Epilepsy typically develops due to a certain genetic defect or often after a presumed precipitating injury. Catamenial epilepsy, in many cases, is assumed to be an acquired disorder and currently there is no clear evidence of genetic components. There is some evidence, however, to suggest that certain intrinsic properties of the brain such as the laterality and focality of the epileptic focus may play a role in the

Conclusions and perspectives

Neurosteroids that enhance the GABAergic neurotransmission are potent anticonvulsants and may regulate various neuronal excitability networks. Neurosteroids are believed to play a role in the regulation of seizure susceptibility in the setting of preexisting epilepsy. Menstrual and stress related fluctuations in seizures may be related to alterations in brain neurosteroid levels. Catamenial epilepsy is a gender-specific form of epilepsy that impacts a substantial proportion (~ 70%) of women with

Conflict of interest statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

The original research described in this article was supported in part by the NIH/NINDS grants NS051398, NS052158, NS071597 and U01NS083460 (to D.S.R.) and the seed grant of the TAMHSC Women's Health in Neuroscience (WHIN) program. The content is solely the responsibility of the author and does not necessarily represent the official views of the NIH.

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