Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

Abstract

Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular steroid receptors. Neuroactive steroids induce potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the γ-amino-butyric type A (GABAA) receptor. They also exert neuroprotective, neurotrophic and antiapoptotic effects in several animal models of neurodegenerative diseases. Neuroactive steroids regulate many physiological functions such as stress response, puberty, ovarian cycle, pregnancy and reward. Their levels are altered in several neuropsychiatric and neurologic diseases and both preclinical and clinical studies emphasise a therapeutic potential of neuroactive steroids for these diseases, whereby symptomatology ameliorates upon restoration of neuroactive steroid concentrations. However, direct administration of neuroactive steroids has several challenges, including pharmacokinetics, low bioavailability, addiction potential, safety and tolerability that limit its therapeutic use. Therefore, modulation of neurosteroidogenesis to restore the altered endogenous neuroactive steroid tone may represent a better therapeutic approach. This review summarizes recent approaches that target the neuroactive steroid biosynthetic pathway at different levels in order to promote neurosteroidogenesis. These include modulation of neurosteroidogenesis through ligands of the translocator protein 18 kDa (TSPO), and the pregnane xenobiotic receptor (PXR), as well as targeting of specific neurosteroidogenic enzymes like 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) or P450 side chain cleavage (P450scc). Enhanced neurosteroidogenesis through these targets may be beneficial for neurodegenerative diseases such as Alzheimer's disease and age-related dementia, but also for neuropsychiatric diseases, including alcohol use disorders.

Cellular and Molecular Mechanisms of the Effects of Sex Hormones on the Nervous System

“…The enzyme 17β-hydroxysteroid dehydrogenase type 10 catalyzes the oxidation of neuroactive steroids in mitochondria with NAD + as the coenzyme. This enzyme catalyzes most effectively the oxidation of allopregnanolone and allotetrahydrodeoxycorticosterone, which is essential for the homeostasis of these neuroactive steroids [8].…”

Ethanol withdrawal-induced dysregulation of neurosteroid levels in plasma, cortex, and hippocampus in genetic animal models of high and low withdrawal

“…Endogenous neurosteroids that rapidly enhance γ-aminobutyric acid A receptor (GABA A R)-mediated inhibition (e.g., Belelli and Lambert, 2005; Carver and Reddy, 2013; Paul and Purdy, 1992) are formed by the 5α-/5β- and then 3α-reduction of the parent steroids progesterone, deoxycorticosterone (DOC), testosterone, and dehydroepiandrosterone (DHEA; e.g., Finn et al, 2004; Porcu et al, 2009, 2016; Snelling et al, 2014). The progesterone metabolites allopregnanolone (ALLO; 3α,5α-THP or tetrahydroprogesterone) and pregnanolone (3α,5β-THP) and the DOC metabolite tetrahydrodeoxycorticosterone (3α,5α-THDOC) are the three most potent neurosteroids characterized to date, as they enhance GABA A R-mediated inhibition with nanomolar (nM) potencies, directly activate GABA A Rs with micromolar potencies, and exert effects on other ligand gated ion channels with micromolar potencies (Belelli and Lambert, 2005; Belelli et al, 1990; Carver and Reddy, 2013; Paul and Purdy, 1992; Purdy et al, 1990; Rupprecht and Holsboer, 1999; Veleiro and Burton, 2009).…”

“…The progesterone metabolites allopregnanolone (ALLO; 3α,5α-THP or tetrahydroprogesterone) and pregnanolone (3α,5β-THP) and the DOC metabolite tetrahydrodeoxycorticosterone (3α,5α-THDOC) are the three most potent neurosteroids characterized to date, as they enhance GABA A R-mediated inhibition with nanomolar (nM) potencies, directly activate GABA A Rs with micromolar potencies, and exert effects on other ligand gated ion channels with micromolar potencies (Belelli and Lambert, 2005; Belelli et al, 1990; Carver and Reddy, 2013; Paul and Purdy, 1992; Purdy et al, 1990; Rupprecht and Holsboer, 1999; Veleiro and Burton, 2009). The testosterone metabolite 3α,5α-androstanediol and the DHEA metabolite 3α,5α-androsterone potentiate GABA A Rs but with lower potency than ALLO and 3α,5α-THDOC (Carver and Reddy, 2013; Porcu et al, 2016). Importantly, all steroidogenic enzymes are localized in the nervous system and in peripheral steroidogenic tissues (Do Rego et al, 2009; Mellon and Vaudry, 2001), indicating that neurosteroid levels in the brain reflect a combination of compounds produced there de novo and from metabolism of circulating precursors.…”

“…Because endogenous levels of ALLO and 3α,5α-THDOC fluctuate in the 10 – 100 nM range that enhance GABA A R inhibition (Barbaccia et al, 2001; Belelli and Lambert, 2005; Carver and Reddy, 2013; Finn et al, 2004; Paul and Purdy, 1992), these neurosteroids can regulate central nervous system (CNS) excitability. Accumulating evidence suggests that dysregulation in neurosteroid synthesis contributes to symptoms in several neuropsychiatric and neurodegenerative diseases and that targeting neurosteroid biosynthesis may be an effective treatment strategy (Porcu et al, 2016). …”

The other side of progestins: effects in the brain

“…An extensively demonstrated progesterone (PROG), produced in peripheral glands as well as directly in the nervous system , Porcu et al 2016, exerts important effects in the neuroendocrine control of reproduction and sexual behavior (Banks & Freeman 1980, Barraclough et al 1986, Skinner et al 1998, Micevych & Sinchak 2008, in the modulation of stress responsiveness and anxietylike behavior (Barbaccia et al 2001 as well as in the regulation of adult neurogenesis (Giachino et al 2003, Wang et al 2008, astroglial, and synaptic plasticity (Luquin et al 1993, McEwen & Woolley 1993, García-Segura et al 1994, Murphy & Segal 2000, Reyna-Neyra et al 2002, Guerra-Araiza et al 2007, Foy et al 2008. Moreover, this steroid regulates the development of some neuronal types (i.e., Purkinje cells of the cerebellum) (Tsutsui et al 2011), oligodendrocytes/Schwann cells (Jung-Testas et al 1996, Ghoumari et al 2005, as well as the myelination process (Chan et al 2000, Melcangi et al 2005, Roglio et al 2008.…”