Neurosteroids in Schizophrenia: Pathogenic and Therapeutic Implications

Abstract

Neurosteroids are a group of important endogenous molecules affecting many neural functions in the brain. Increasing evidence suggests a possible role of these neurosteroids in the pathology and symptomatology of schizophrenia (SZ) and other mental disorders. The aim of this review is to summarize the current knowledge about the neural functions of neurosteroids in the brain, and to evaluate the role of the key neurosteroids as candidate modulators in the etiology and therapeutics of SZ. The present paper provides a brief introduction of neurosteroid metabolism and distribution, followed by a discussion of the mechanisms underlying neurosteroid actions in the brain. The content regarding the modulation of the GABA_A receptor is elaborated, given the considerable knowledge of its interactions with other neurotransmitter and neuroprotective systems, as well as its ameliorating effects on stress that may play a role in the SZ pathophysiology. In addition, several preclinical and clinical studies suggested a therapeutic benefit of neurosteroids in SZ patients, even though the presence of altered neurosteroid pathways in the circulating blood and/or brain remains debatable. Following treatment of antipsychotic drugs in SZ, therapeutic benefits have also been linked to the regulation of neurosteroid signaling. Specifically, the neurosteroids such as pregnenolone and dehydroepiandrosterone affect a broad spectrum of behavioral functions through their unique molecular characteristics and may represent innovative therapeutic targets for SZ. Future investigations in larger cohorts with long-term follow-ups will be required to ascertain the neuropsychopharmacological role of this yet unexploited class of neurosteroid agents.

Keywords: GABAA receptor; clinical trial as topic; metabolism; neurosteroids; schizophrenia.

Figure 1

The biosynthesis pathways of neurosteroids in the human brain. Abbreviations: AROM, aromatase; HST, sulfotransferase; STS, sulfatase; P450scc, cytochrome P450 side-chain cleavage; P450c11, cytochrome P450 11β-hydroxylase/18-hydroxylase/18-methyl oxidase; P450c17, cytochrome P450 17α-hydroxylase/17,20-lyase; P450c21, cytochrome P450 21-hydroxylase; 3α-HSD, 3α-hydroxysteroid dehydrogenase; 3β-HSD, 3β-hydroxysteroid dehydrogenase; 5α-R, 5α-reductase; 17β-HSD, 17β-hydroxysteroid dehydrogenase. Those neurosteroids having the potential therapeutic roles in schizophrenia are highlighted in red in the figure.

Figure 2

Schematic representation of the GABA_A receptor complex. Postsynatpic GABA_A receptors, which are pentameric chloride channels consisting of two α, two β, and one γ subunits, mediated the phasic GABAergic inhibition, whereas extrasynaptic GABA_A receptors, pentamers composed of two α, two β, and one δ subunits, primarily contribute to tonic inhibition. Neurosteroids activate both postsynaptic and extrasynaptic receptors to enhance the phasic and tonic inhibition, and thereby promote maximal net inhibition. The GABA_A receptors have distinct binding sites for numerous molecules, as illustrated in the figure. The typical neurosteroids that modulate positively (+) or negatively (−) on the GABA_A receptor complex at the synaptic membrane of nerve cells are indicated. The red dots represent the GABA neurotransmitter molecules released from the vesicles of the GABA neuron synapse. Abbreviations: GABA, γ-aminobutyric acid; THDOC, tetrahydrodeoxycorticosterone; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate.

Figure 3

Features of general neurosteroid structure with the rings and carbon positions labeled. Hydroxyl groups are denoted β if they are oriented above the plane (solid line) and α if they are oriented below the plane (dashed line). GABA_A receptor-activated neurosteroids have the following structural requirements as highlighted with red rounded rectangle: (1) the scaffold geometry at the A/B ring; (2) a hydrogen-bond donator in C3 position which is indispensable for the binding affinity and the enhancing functions of neurosteroids; (3) the stereoselectivity of C5α-H which may affect the potency of the neuorsteroids; and (4) a hydrogen-bond acceptor in C20 position or a flexible bond at C17 position is important for high-potency positive allosteric modulation.

Figure 4

Neurosteroids and schizophrenia (SZ). Unknown SZ pathology, genetic liability, and/or environmental stress may lead to disrupted neurosteroidgenesis, which is manifested by abnormalities in several key neurosteroids, including pregnenolone (PREG), PREG sulfate, dehydroepiandrosterone (DHEA), DHEA sulfate, progesterone (PROG), and allopregnanolone (ALLO). This disruption is associated with dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, aggravated anxiety, and negative symptoms, as well as impairment in cognition. Some of the symptom domains can be reversed with neurosteroid argumentation. 5α-reductase (5α-R) is a rate-limiting enzyme involved in neurosteroid metabolism. Recent pharmacological studies revealed that the inhibition of 5α-R activity by 5α-R inhibitor could prevent quick exhaustion of the aforementioned neurosteroids. Thus, 5α-R may be a new promising target for SZ treatment. ↑ indicates increased and ↓ indicates decreased.