Charles F. Zorumski , Douglas F. Covey , Yukitoshi Izumi , Alex S. Evers , Jamie L. Maguire , Steven J. Mennerick
{"title":"New directions in neurosteroid therapeutics in neuropsychiatry","authors":"Charles F. Zorumski , Douglas F. Covey , Yukitoshi Izumi , Alex S. Evers , Jamie L. Maguire , Steven J. Mennerick","doi":"10.1016/j.neubiorev.2025.106119","DOIUrl":null,"url":null,"abstract":"<div><div>In recent years three neuroactive steroids (NAS), brexanolone (allopregnanolone, AlloP), ganaxolone and zuranolone, have been approved for the treatment of neuropsychiatric illnesses including postpartum depression and seizures in a neurodevelopmental syndrome. The approved agents are pregnane steroids and strong positive allosteric modulators (PAMs) of gamma-aminobutyric acid type A receptors (GABA<sub>A</sub>Rs). Broad effects on GABA<sub>A</sub>Rs play important roles in therapeutic benefits. However, these NAS also have actions on non-GABAR targets that could be important for clinical outcomes. Thus, understanding the broader effects of NAS is potentially important for expanding the therapeutic landscape of these important modulators. The approved NAS as well as other structurally distinct NAS and oxysterols have effects on non-GABA<sub>A</sub>R receptors and ion channels, along with intracellular actions that could have therapeutic importance, including modulation of cellular stress mechanisms, neuroinflammation, mitochondrial function and autophagy, among others. In this review, we explore GABAergic and other cellular effects of pregnane steroids including novel molecules that have potential therapeutic importance. This work discusses the complex chemical nature of NAS and what is being learned at cellular, molecular, synaptic and brain network levels about key sites of action including GABA<sub>A</sub>Rs and other targets.</div></div>","PeriodicalId":56105,"journal":{"name":"Neuroscience and Biobehavioral Reviews","volume":"172 ","pages":"Article 106119"},"PeriodicalIF":7.5000,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuroscience and Biobehavioral Reviews","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0149763425001198","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BEHAVIORAL SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
In recent years three neuroactive steroids (NAS), brexanolone (allopregnanolone, AlloP), ganaxolone and zuranolone, have been approved for the treatment of neuropsychiatric illnesses including postpartum depression and seizures in a neurodevelopmental syndrome. The approved agents are pregnane steroids and strong positive allosteric modulators (PAMs) of gamma-aminobutyric acid type A receptors (GABAARs). Broad effects on GABAARs play important roles in therapeutic benefits. However, these NAS also have actions on non-GABAR targets that could be important for clinical outcomes. Thus, understanding the broader effects of NAS is potentially important for expanding the therapeutic landscape of these important modulators. The approved NAS as well as other structurally distinct NAS and oxysterols have effects on non-GABAAR receptors and ion channels, along with intracellular actions that could have therapeutic importance, including modulation of cellular stress mechanisms, neuroinflammation, mitochondrial function and autophagy, among others. In this review, we explore GABAergic and other cellular effects of pregnane steroids including novel molecules that have potential therapeutic importance. This work discusses the complex chemical nature of NAS and what is being learned at cellular, molecular, synaptic and brain network levels about key sites of action including GABAARs and other targets.
期刊介绍:
The official journal of the International Behavioral Neuroscience Society publishes original and significant review articles that explore the intersection between neuroscience and the study of psychological processes and behavior. The journal also welcomes articles that primarily focus on psychological processes and behavior, as long as they have relevance to one or more areas of neuroscience.