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.

Gut feelings: the microbiota-gut-brain axis on steroids

“…The neural impact of steroids may also be regulated by altered enzymatic activity modulating their synthesis. Several reviews have described how sex hormone-related steroidogenesis is carried out in the nervous system (136) (140) (54). In brief, cholesterol is transported across the mitochondrial membrane, a process regulated by steroidogenic acute regulatory protein (StAR) and translocator protein (TSPO).…”

Effect of Allopregnanolone on Spatial Memory and Synaptic Proteins in Animal Model of Metabolic Syndrome

“…It worth noting that Allopregnanolone was approved in the united states of America for the treatment of postpartum depression [ 45 ]. Allopregnanolone is a positive modulator of GABAAR activity [ 5 ]. GABA is the primary inhibitory neurotransmitter in the brain and plays a vital role in learning and memory [ 46 ] and synaptic plasticity [ 47 ].…”

“…Neurosteroids are steroid hormones synthesized de novo in the brain and peripheral nervous tissues [ 5 ]. Allopregnanolone is an essential neurosteroid in the brain, synthesized locally or in the periphery, and reaches the brain by crossing the blood-brain barrier [ 6 ].…”

Alterations of Cytochrome P450s and UDP-Glucuronosyltransferases in Brain Under Diseases and Their Clinical Significances

“…The 5α-reductase enzyme first converts progesterone to 5α-dihydroprogesterone, which is further metabolized by 3α-hydroxysteroid dehydrogenase to form allopregnanolone. Allopregnanolone, acting as a potent endogenous positive allosteric modulator of gamma-aminobutyric acid (GABA) A receptor, regulates emotional behaviors, reducing brain excitability and eliciting sedative-hypnotic, anxiolytic, and anticonvulsant effects ( Yilmaz et al, 2019 ; Lloyd-Evans and Waller-Evans, 2020 ). Allopregnanolone has been approved for treatment of postpartum depression ( Zorumski et al, 2019 ).…”