Biosynthesis and signalling functions of central and peripheral nervous system neurosteroids in health and disease

Abstract

Neurosteroids are steroid hormones synthesised de novo in the brain and peripheral nervous tissues. In contrast to adrenal steroid hormones that act on intracellular nuclear receptors, neurosteroids directly modulate plasma membrane ion channels and regulate intracellular signalling. This review provides an overview of the work that led to the discovery of neurosteroids, our current understanding of their intracellular biosynthetic machinery, and their roles in regulating the development and function of nervous tissue. Neurosteroids mediate signalling in the brain via multiple mechanisms. Here, we describe in detail their effects on GABA (inhibitory) and NMDA (excitatory) receptors, two signalling pathways of opposing function. Furthermore, emerging evidence points to altered neurosteroid function and signalling in neurological disease. This review focuses on neurodegenerative diseases associated with altered neurosteroid metabolism, mainly Niemann-Pick type C, multiple sclerosis and Alzheimer disease. Finally, we summarise the use of natural and synthetic neurosteroids as current and emerging therapeutics alongside their potential use as disease biomarkers.

Keywords: Alzheimers disease; GABA; Neurosteroid; Niemann Pick type C; glutamate receptor; multiple sclerosis.

Figure 1. IUPAC and common nomenclature of certain pregnane, androstane and sulphated neurosteroids

Figure 2. The central and peripheral nervous system biosynthetic pathway of neurosteroids

The process is activated by transport of cholesterol into mitochondria by StAR and continues in the endoplasmic reticulum following production of progesterone. Biosynthetic enzymes are denoted in blue, neurosteroids in black and enzymes involved in sulphation in red. Note, synthesis *only reported in astrocytes, **only reported in Purkinje cells, ***only reported in microglia. Abbreviations: AllotetrahydroDOC, allotetrahydrodeoxycorticosterone; DHEAS, dehydroepiandrosterone sulphate; DHT, 5α-dihydrotestosterone; P450c11β, sterol 11β-hydroxylase; P450c21, steroid 21-hydroxylase; PREGS, pregnenolone sulphate; TetrahydroDOC, tetrahydrodeoxycorticosterone.

Figure 3. Synthetic neurosteroids used in therapeutic studies and their natural neurosteroid analogue