Neurosteroids as stress modulators and neurotherapeutics:lessons from the retina
Yukitoshi Izumi1
Makoto Ishikawa2
Toru Nakazawa3
Hiroshi Kunikata4
Kota Sato5
Douglas F.Covey6
Charles F.Zorumski1
1.Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research,Washington University School of Medicine,St.Louis,MO,USA2.Department of Ophthalmic Imaging and Information Analytics,Tohoku University Graduate School of Medicine,Sendai,Japan;Department of Ophthalmology,Tohoku University Graduate School of Medicine,Sendai,Japan3.Department of Ophthalmic Imaging and Information Analytics,Tohoku University Graduate School of Medicine,Sendai,Japan;Department of Ophthalmology,Tohoku University Graduate School of Medicine,Sendai,Japan;Department of Retinal Disease Control,Tohoku University Graduate School of Medicine,Sendai,Japan;Department of Advanced Ophthalmic Medicine,Tohoku University Graduate School of Medicine,Sendai,Japan4.Department of Ophthalmology,Tohoku University Graduate School of Medicine,Sendai,Japan;Department of Retinal Disease Control,Tohoku University Graduate School of Medicine,Sendai,Japan5.Department of Ophthalmic Imaging and Information Analytics,Tohoku University Graduate School of Medicine,Sendai,Japan;Department of Advanced Ophthalmic Medicine,Tohoku University Graduate School of Medicine,Sendai,Japan6.Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research,Washington University School of Medicine,St.Louis,MO,USA;Department of Developmental Biology,Washington University School of Medicine,St.Louis,MO,USA
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.
机标关键词：stressfromlessonsmodulatorsneurosteroidsretinatherapeutics
论文发表日期：2023-05-28
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：5( 1004-1008 )
英文信息