Neurosteroids as stress modulators and neurotherapeutics: lessons from the retina

作     者：Yukitoshi Izumi Makoto Ishikawa Toru Nakazawa Hiroshi Kunikata Kota Sato Douglas F.Covey Charles F.Zorumski Yukitoshi Izumi;Makoto Ishikawa;Toru Nakazawa;Hiroshi Kunikata;Kota Sato;Douglas F.Covey;Charles F.Zorumski

作者机构：Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric ResearchWashington University School of MedicineSt.LouisMOUSA Department of Ophthalmic Imaging and Information AnalyticsTohoku University Graduate School of MedicineSendaiJapan Department of OphthalmologyTohoku University Graduate School of MedicineSendaiJapan Department of Retinal Disease ControlTohoku University Graduate School of MedicineSendaiJapan Department of Advanced Ophthalmic MedicineTohoku University Graduate School of MedicineSendaiJapan Department of Developmental BiologyWashington University School of MedicineSt.LouisMOUSA 

出 版 物：《Neural Regeneration Research》 (中国神经再生研究（英文版）)

年 卷 期：2023年第18卷第5期

页      面：1004-1008页

核心收录：

学科分类：1002[医学-临床医学] 100212[医学-眼科学] 10[医学] 

基　　金：supported by MH101874, MH114866, MH122379 from the National Institute of Mental Health (to CFZ) the Taylor Family Institute for Innovative Psychiatric Research and the Bantly Foundation (to CFZ) 

主　　题：allopregnanolone autophagy enantiomers excitotoxicity gamma-aminobutyric acid type A receptors glaucoma optic nerve oxysterols 

摘      要：Neurosteroids are rapidly emerging as important new therapies in neuropsychiatry, with one such agent, brexanolone, already approved for treatment of postpartum depression, and others on the horizon. These steroids have unique properties, including neuroprotective effects that could benefit a wide range of brain illnesses including depression, anxiety, epilepsy, and neurodegeneration. Over the past 25 years, our group has developed ex vivo rodent models to examine factors contributing to several forms of neurodegeneration in the retina. In the course of this work, we have developed a model of acute closed angle glaucoma that involves incubation of ex vivo retinas under hyperbaric conditions and results in neuronal and axonal changes that mimic glaucoma. We have used this model to determine neuroprotective mechanisms that could have therapeutic implications. In particular, we have focused on the role of both endogenous and exogenous neurosteroids in modulating the effects of acute high pressure. Endogenous allopregnanolone, a major stress-activated neurosteroid in the brain and retina, helps to prevent severe pressure-induced retinal excitotoxicity but is unable to protect against degenerative changes in ganglion cells and their axons under hyperbaric conditions. However, exogenous allopregnanolone, at a pharmacological concentration, completely preserves retinal structure and does so by combined effects on gamma-aminobutyric acid type A receptors and stimulation of the cellular process of macroautophagy. Surprisingly, the enantiomer of allopregnanolone, which is inactive at gamma-aminobutyric acid type A receptors, is equally retinoprotective and acts primarily via autophagy. Both enantiomers are also equally effective in preserving retinal structure and function in an in vivo glaucoma model. These studies in the retina have important implications for the ongoing development of allopregnanolone and other neurosteroids as therapeutics for neuropsychiatric illnesses.