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

2020 ◽  
Vol 64 (3) ◽  
pp. 591-606 ◽  
Author(s):  
Emyr Lloyd-Evans ◽  
Helen Waller-Evans
Keyword(s):  
Steroid Hormones ◽  
De Novo ◽  
Adrenal Steroid ◽  
Disease Biomarkers ◽  
Health And Disease ◽  
Type C ◽  
Niemann Pick ◽  
And Function ◽  
The Brain ◽  
Biosynthetic Machinery

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.

scholarly journals Thyroid Hormone and the Neuroglia: Both Source and Target

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Petra Mohácsik ◽  
Anikó Zeöld ◽  
Antonio C. Bianco ◽  
Balázs Gereben
Keyword(s):  
Thyroid Hormone ◽  
Cell Function ◽  
Hormone Regulation ◽  
Mediobasal Hypothalamus ◽  
Iodothyronine Deiodinase ◽  
Neuronal Gene ◽  
Health And Disease ◽  
And Function ◽  
The Brain

Thyroid hormone plays a crucial role in the development and function of the nervous system. In order to bind to its nuclear receptor and regulate gene transcription thyroxine needs to be activated in the brain. This activation occurs via conversion of thyroxine to T3, which is catalyzed by the type 2 iodothyronine deiodinase (D2) in glial cells, in astrocytes, and tanycytes in the mediobasal hypothalamus. We discuss how thyroid hormone affects glial cell function followed by an overview on the fine-tuned regulation of T3 generation by D2 in different glial subtypes. Recent evidence on the direct paracrine impact of glial D2 on neuronal gene expression underlines the importance of glial-neuronal interaction in thyroid hormone regulation as a major regulatory pathway in the brain in health and disease.

scholarly journals Myelin Defects in Niemann–Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives

2021 ◽  
Vol 22 (16) ◽  
pp. 8858
Author(s):  
Antonietta Bernardo ◽  
Chiara De Nuccio ◽  
Sergio Visentin ◽  
Alberto Martire ◽  
Luisa Minghetti ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Autophagic Flux ◽  
Unesterified Cholesterol ◽  
A2a Adenosine Receptor ◽  
Disease Mechanisms ◽  
Mitochondrial Functions ◽  
Type C ◽  
Niemann Pick ◽  
Cellular Compartments ◽  
The Brain

Niemann–Pick type C (NPC) disease is a wide-spectrum clinical condition classified as a neurovisceral disorder affecting mainly the liver and the brain. It is caused by mutations in one of two genes, NPC1 and NPC2, coding for proteins located in the lysosomes. NPC proteins are deputed to transport cholesterol within lysosomes or between late endosome/lysosome systems and other cellular compartments, such as the endoplasmic reticulum and plasma membrane. The first trait of NPC is the accumulation of unesterified cholesterol and other lipids, like sphingosine and glycosphingolipids, in the late endosomal and lysosomal compartments, which causes the blockade of autophagic flux and the impairment of mitochondrial functions. In the brain, the main consequences of NPC are cerebellar neurodegeneration, neuroinflammation, and myelin defects. This review will focus on myelin defects and the pivotal importance of cholesterol for myelination and will offer an overview of the molecular targets and the pharmacological strategies so far proposed, or an object of clinical trials for NPC. Finally, it will summarize recent data on a new and promising pharmacological perspective involving A2A adenosine receptor stimulation in genetic and pharmacological NPC dysmyelination models.

scholarly journals Sex Differences and the Influence of Sex Hormones on Cognition through Adulthood and the Aging Process

2018 ◽  
Vol 8 (9) ◽  
pp. 163 ◽  
Author(s):  
Caroline Gurvich ◽  
Kate Hoy ◽  
Natalie Thomas ◽  
Jayashri Kulkarni
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sex Differences ◽  
Cognitive Functioning ◽  
Sex Hormones ◽  
Reproductive Function ◽  
Health And Disease ◽  
And Function ◽  
The Brain

Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain. Sex differences in cognitive functioning have been reported in both health and disease, which may be partly attributed to sex hormones. The aim of the current paper was to provide a theoretical review of how sex hormones influence cognitive functioning across the lifespan as well as provide an overview of the literature on sex differences and the role of sex hormones in cognitive decline, specifically in relation to Alzheimer’s disease (AD). A summary of current hormone and sex-based interventions for enhancing cognitive functioning and/or reducing the risk of Alzheimer’s disease is also provided.

Genetic defects in sterol synthesis, absorption, and degradation into bile acids

2011 ◽  
pp. 1673-1676
Author(s):  
Stefano Romeo
Keyword(s):  
Membrane Permeability ◽  
Bile Acids ◽  
Steroid Hormones ◽  
Cell Membranes ◽  
De Novo ◽  
Cholesterol Metabolism ◽  
The Body ◽  
Sterol Synthesis ◽  
Genetic Defects ◽  
And Function

Cholesterol is the most abundant steroid in animals. Not only is it a vital constituent of cell membranes, where it establishes proper membrane permeability and fluidity, but it is also the immediate metabolic precursor of all known steroid hormones and bile acids. Synthesized de novo in cells or absorbed from the diet, cholesterol circulates in the body in association with lipoproteins and is ultimately degraded into bile acids by the liver. Every perturbation of the numerous enzymes involved in cholesterol metabolism leads to impairment in the development and function of the gastrointestinal, cardiovascular, skeletal, and nervous systems.

Apoptosis accompanied by up-regulation of TNF-α death pathway genes in the brain of Niemann–Pick type C disease

2005 ◽  
Vol 84 (1) ◽  
pp. 9-17 ◽  
Author(s):  
Yun-Ping Wu ◽  
Hiroki Mizukami ◽  
Junko Matsuda ◽  
Yuko Saito ◽  
Richard L. Proia ◽  
...  
Keyword(s):  
Tnf Α ◽  
Type C ◽  
Niemann Pick ◽  
The Brain

Sex Differences Shape Brain Development and Function, in Health and Disease: Policy Implications

2017 ◽  
Vol 5 (1) ◽  
pp. 104-109 ◽  
Author(s):  
Staci D. Bilbo
Keyword(s):  
Sex Differences ◽  
Autism Spectrum ◽  
Policy Implications ◽  
Female Ratio ◽  
Brain Sciences ◽  
Health And Disease ◽  
Fundamental Research ◽  
And Function ◽  
Sex Disparity ◽  
The Brain

Sex differences profoundly impact health and disease. Despite this, the inclusion of females in clinical and fundamental research lags far behind advances in other aspects of medicine, especially in the brain sciences. Regardless of whether neuroscientists are intrinsically interested in sex differences per se, observing a sex disparity in the incidence or presentation of a given neurological disorder provides a significant clue into the neurobiology of that disorder. Autism spectrum disorder (ASD) is one of the most sex-biased disorders, with a 4:1 male-to-female ratio, an important aspect of its etiology and biology that has largely been ignored in the preclinical literature. This article briefly overviews what is known about the sexual differentiation of the developing healthy brain, with a focus on the preclinical literature. This places observed sex differences in neurological disorders such as ASD into the context of known sex differences in neurobiology—along with insight from known sex-specific mechanisms in other systems that impact the brain (e.g., immune system, microbiome). Finally, the article provides recommendations for progress forward.

scholarly journals Generation and function of astroglial lipoproteins from Niemann–Pick type C1-deficient mice

2005 ◽  
Vol 387 (3) ◽  
pp. 779-788 ◽  
Author(s):  
Barbara KARTEN ◽  
Hideki HAYASHI ◽  
Gordon A. FRANCIS ◽  
Robert B. CAMPENOT ◽  
Dennis E. VANCE ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
Cell Types ◽  
Apolipoprotein A1 ◽  
Functional Assay ◽  
Atp Binding Cassette Transporter ◽  
Apo E ◽  
Type C ◽  
Niemann Pick ◽  
And Function ◽  
Endosomal System

NPC (Niemann–Pick type C) disease is a progressive neurological disorder characterized by defects in intracellular cholesterol trafficking, accumulation of cholesterol in the endosomal system and impaired cholesterol homoeostasis. Although these alterations appear to occur in all NPC1-deficient cell types, the consequences are most profound in the nervous system. Since glial cells are important mediators of brain cholesterol homoeostasis, we proposed that defective generation and/or function of lipoproteins released by glia might contribute to the neurological abnormalities associated with NPC disease. We found that, as in other cell types, Npc1−/− glia accumulate cholesterol intracellularly. We hypothesized that this sequestration of cholesterol in glia might restrict the availability of cholesterol for lipoprotein production. Cerebellar astroglia were cultured from a murine model of NPC disease to compare the lipoproteins generated by these cells and wild-type glia. The experiments demonstrate that the amount of cholesterol in glia-conditioned medium is not reduced by NPC1 deficiency. Similarly, cholesterol efflux to apo (apolipoprotein) A1 or glial expression of the transporter ATP-binding-cassette transporter A1 was not decreased by NPC1 deficiency. In addition, the ratio of apo E:cholesterol and the density distribution of lipoproteins in Npc1−/− and Npc1+/+ glia-conditioned medium are indistinguishable. Importantly, in a functional assay, apo E-containing lipoproteins generated by Npc1−/− and Npc1+/+ glia each stimulate axonal elongation of neurons by approx. 35%. On the basis of these observations, we speculate that the neuropathology characteristic of NPC disease can quite probably be ascribed to impaired processes within neurons in the brain rather than defective lipoprotein production by astroglia.

scholarly journals Functional neuroimaging as a direct probe of the effects of gonadal steroid hormones on the brain

2002 ◽  
Vol 4 (2) ◽  
pp. 192-195
Keyword(s):  
Steroid Hormones ◽  
Animal Studies ◽  
Functional Neuroimaging ◽  
Functional Brain Imaging ◽  
Neural Function ◽  
Gonadal Steroid Hormones ◽  
Gonadal Steroid ◽  
Neurophysiological Data ◽  
Health And Disease ◽  
The Brain

There is considerable evidence from animal studies dial gonadal steroid hormones modulate neuronal activity and affect behavior. In humans, however, the behavioral and cognitive evidence has not been conclusive, and, until recently, there have been few direct neurophysiological data. Functional brain imaging offers unique opportunities to characterize in humans the effects of gonadal steroid hormones on basic neurobiological parameters, such as neuronal metabolism and neurochemical systems, and to clarify the interactions between these hormones and cognition and mood regulation in health and disease. The most commonly used tools within the considerable armamentarium available for such research and the parameters of neural function that they can access are briefly reviewed here.

scholarly journals The Fruit Fly Drosophila melanogaster as a Model System to Study Cholesterol Metabolism and Homeostasis

Cholesterol ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Ryusuke Niwa ◽  
Yuko S. Niwa
Keyword(s):  
Drosophila Melanogaster ◽  
Steroid Hormones ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Fruit Fly ◽  
Model System ◽  
Biophysical Properties ◽  
Type C ◽  
Niemann Pick

Cholesterol has long been recognized for its versatile roles in influencing the biophysical properties of cell membranes and for serving as a precursor of steroid hormones. While many aspects of cholesterol biosynthesis are well understood, little is currently known about the molecular mechanisms of cholesterol metabolism and homeostasis. Recently, genetic approaches in the fruit fly, Drosophila melanogaster, have been successfully used for the analysis of molecular mechanisms that regulate cholesterol metabolism and homeostasis. This paper summarizes the recent studies on genes that regulate cholesterol metabolism and homeostasis, including neverland, Niemann Pick type C(NPC) disease genes, and DHR96.

scholarly journals Neurosteroids and GABAergic signaling in health and disease

2013 ◽  
Vol 4 (1) ◽  
pp. 29-42 ◽  
Author(s):  
Georgina MacKenzie ◽  
Jamie Maguire
Keyword(s):  
Sexual Behaviors ◽  
Neuronal Excitability ◽  
De Novo ◽  
Aminobutyric Acid ◽  
Acid Type ◽  
Direct Binding ◽  
Health And Disease ◽  
Local Metabolism ◽  
The Brain ◽  
Large Charge

AbstractEndogenous neurosteroids such as allopregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol are synthesized either de novo in the brain from cholesterol or are generated from the local metabolism of peripherally derived progesterone or corticosterone. Fluctuations in neurosteroid concentrations are important in the regulation of a number of physiological responses including anxiety and stress, reproductive, and sexual behaviors. These effects are mediated in part by the direct binding of neurosteroids to γ-aminobutyric acid type-A receptors (GABAARs), resulting in the potentiation of GABAAR-mediated currents. Extrasynaptic GABAARs containing the δ subunit, which contribute to the tonic conductance, are particularly sensitive to low nanomolar concentrations of neurosteroids and are likely their preferential target. Considering the large charge transfer generated by these persistently open channels, even subtle changes in neurosteroid concentrations can have a major impact on neuronal excitability. Consequently, aberrant levels of neurosteroids have been implicated in numerous disorders, including, but not limited to, anxiety, neurodegenerative diseases, alcohol abuse, epilepsy, and depression. Here we review the modulation of GABAAR by neurosteroids and the consequences for health and disease.

Sign in / Sign up

Export Citation Format

Share Document