Neurosteroids as stress modulators and neurotherapeutics: lessons from the retina.
Neurosteroids as stress modulators and neurotherapeutics: lessons from the retina.
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DOI：
10.4103/1673-5374.355752
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发表时间：
2023-05
影响因子：
6.1
通讯作者：
Zorumski CF
中科院分区：
文献类型：
--
作者：
Izumi Y;Ishikawa M;Nakazawa T;Kunikata H;Sato K;Covey DF;Zorumski CF
神经类固醇正在迅速成为神经精神病学中重要的新疗法，其中一种药物布雷沙诺龙已经被批准用于治疗产后抑郁症，其他药物也即将问世。这些类固醇具有独特的性质，包括神经保护作用，可能有益于包括抑郁、焦虑、癫痫和神经变性在内的一系列脑部疾病。在过去的25年里，我们的团队开发了体外啮齿动物模型，以研究导致视网膜几种形式的神经变性的因素。在这项工作的过程中，我们建立了一个急性闭角型青光眼模型，包括在高压条件下孵育体外视网膜，并导致类似青光眼的神经元和轴突变化。我们已经使用这个模型来确定可能具有治疗意义的神经保护机制。特别是，我们关注了内源性和外源性神经类固醇在调节急性高压效应中的作用。内源性别孕酮是大脑和视网膜中的一种主要的应激激活神经类固醇，有助于预防严重的压力诱导的视网膜兴奋毒性，但无法防止高压条件下神经节细胞及其轴突的退行性变化。然而，外源性别孕酮在一定的药理浓度下，完全保留了视网膜的结构，并通过联合作用于γ-氨基丁酸A型受体和刺激巨细胞自噬的过程来做到这一点。令人惊讶的是，别孕酮的对映体在γ-氨基丁酸A型受体上不起作用，同样具有视黄醇保护作用，主要通过自噬发挥作用。在活体青光眼模型中，这两种对映体在保护视网膜结构和功能方面也同样有效。这些视网膜研究对别孕酮和其他神经类固醇作为治疗神经精神疾病的药物的持续发展具有重要意义。
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.
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影响因子：
25.8
作者：
Alnaes, Dag;Kaufmann, Tobias;Westlye, Lars T.
通讯作者：
Westlye, Lars T.
影响因子：
5.6
作者：
Ishikawa M;Nakazawa T;Kunikata H;Sato K;Yoshitomi T;Krishnan K;Covey DF;Zorumski CF;Izumi Y
通讯作者：
Izumi Y
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Purdy, RH
影响因子：
2.5
作者：
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通讯作者：
Mennerick, Steven