Neurosteroids and neurological disorders

Abstract

Neurosteroids play an important role as endogenous neuromodulators that are locally produced in the central nervous system and rapidly change the excitability of neurons and the activation of microglial cells and astrocytes. Here we review the mechanisms of synthesis, metabolism, and actions of neurosteroids in the central nervous system. Neurosteroids are able to play a variety of roles in the central nervous system under physiological conditions by binding to membrane ion channels and receptors such as gamma-aminobutyric acid type A receptors, Nmethyl- D-aspartate receptors, L- and T-type calcium channels, and sigma-1 receptors. In addition, numerous neurological disorders, including persistent neuropathic pain, multiple sclerosis, and seizures, have altered the levels of neurosteroids in the central nervous system. Thus, we review how local synthesis and metabolism of neurosteroids are modulated in the central nervous system and describe the role of neurosteroids under pathological conditions. Furthermore, we discuss whether neurosteroids may play a role as a new therapeutic for the treatment of neurological disorders.

Keywords: GABA; N-methyl-D-aspartate; Nervous system diseases; Neurosteroids; Receptors; Sigma-1 receptor.

Fig. 1. Schematic diagram of the steps in the steroidogenesis of progesterone.

Cholesterol is synthesized from low density lipoprotein (LDL) by lysosomal acid lipase (LAL) or from acetyl CoA molecules. Steroidogenic acute regulatory protein (StAR) transfers cholesterol from cytoplasm into the mitochondria across the outer and inner mitochondrial membranes. Cholesterol is converted to pregnenolone by cytochrome P450side chain cleavage (P450scc), and pregnenolone is metabolized to progesterone by 3β-hydroxysteroid dehydrogenase (3β-HSD).

Fig. 2. Outline of neurosteroidogenesis.

Cytochrome P450side chain cleavage (P450scc) converts cholesterol to pregnenolone, which is metabolized to progesterone by 3β-hydroxysteroid dehydrogenase (3β-HSD) or to dehydroepiandrosterone (DHEA) by cytochrome P450c17 (P450c17). Progesterone is metabolized to allopregnanolone by 5α-reductase (5α-R) and 3α-hydroxysteroid oxidoreductase (3α-HSOR) or to androstenedione by P450c17. Aromatase converts androstenedione to estrone, which is metabolized to estradiol by 17β-hydroxysteroid dehydrogenase (17β-HSD), and synthesizes estradiol from testosterone. DHP, dihydroprogesterone; DHT, dihydrotestosterone; 17-OH-PREG, 17-OH-pregnenolone; 17-OH-PROG, 17-OH-progesterone.