Neuroactive steroids as novel psychiatric treatments: mechanistic studies

神经活性类固醇作为新型精神病治疗：机制研究

基本信息

批准号：
10662398
负责人：
STEVEN J MENNERICK
金额：
$ 242.7万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662398
关键词：
Allopregnanolone Antidepressive Agents Behavior Behavioral Biological Biology Brain Calcium Channel Catalogs Cause of Death Cell physiology Cellular Stress Chemistry Collaborations Complement Data Development Disease Enhancers FDA approved Formulation Fostering Funding Future GABA Agents Glutamate Receptor Goals Health Hippocampus Inflammation Inflammatory International Ion Channel Ketamine Ligands Major Depressive Disorder Mass Spectrum Analysis Mediating Medical Mental disorders Modernization Molecular Molecular Target Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurons Oral Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase Photoaffinity Labels Positioning Attribute Postpartum Depression Postpartum Period Productivity Psychiatric therapeutic procedure Recording of previous events Research Research Personnel Research Support Resources Role Scientist Seminal Site Steroids Stress Structure Synapses Testing Therapeutic Therapeutic Effect Translational Research Woman Work analog antidepressant effect cell type disability drug development experience gamma-Aminobutyric Acid improved innovation insight member men mouse model multidisciplinary neural circuit neural network neuroinflammation neurosteroids novel novel therapeutics pharmacologic phase 3 study programs prototype receptor side effect steroid analog success therapeutic development tool voltage

项目摘要

CONTE CENTER SUMMARY Neuroactive steroids (NAS) offer novel directions for psychiatric therapeutics. The prototypical NAS is allopregnanolone (AlloP), which under the formulation of brexanolone, has recently been approved by FDA for treatment of women with postpartum depression; a second, orally-active NAS has had a successful Phase 3 study for postpartum depression and a Phase 2B study for men and women with major depression. While AlloP is a potent and effective enhancer of GABAA receptors (GABAARs), it is not presently clear that the antidepressant effects of NAS are mediated solely by GABAergic effects, and recent data indicate that other mechanisms including effects on cellular stress and inflammatory pathways could also be involved. Members of our center have extensive experience studying the medicinal chemistry and mechanisms underlying the effects of AlloP-like NAS. In this Conte Center proposal we will leverage novel NAS compounds to probe varied molecular, synaptic, network and behavioral effects of NAS as clues to their therapeutic mechanisms and potential. Our center proposal is driven by unique NAS analogues synthesized in our Chemistry Core and involves three complementary and intertwined projects that will pursue three specific goals. First, we will test the hypothesis that selective actions of NAS on a class of GABAARs underlies effects on hippocampal electrical activity, network function and behavior in novel mouse lines and mouse models of postpartum and major depression. Second, we will examine the role of non-GABAA ion channels in mediating hippocampal and behavioral effects of NAS focusing on novel NAS that modulate NMDA glutamate receptors and low voltage activated calcium channels. These studies will use unique photoaffinity labeling approaches to elucidate sites of actions of NAS on NMDA receptors and other targets. Other studies will examine effects of NAS analogues on cellular function, neural network function, and behavior. Third, we will test the role of intracellular targets engaged by NAS on hippocampal circuits and behavior, focusing on the roles of neuroinflammation and cellular stress pathways. Our center is uniquely positioned to traverse the exploration of antidepressant NAS from molecules to sites of action and effects on dysfunctional circuits to identify potentially novel agents and targets for psychiatric therapeutic development.

内容中心概要神经活性类固醇（NAS）为精神科治疗提供了新的方向。 NAS 的原型是 allopregnanolone (AlloP) 的配方为 brexanolone，最近已获得 FDA 批准用于治疗患有产后抑郁症的妇女；第二个口服活性 NAS 已成功针对产后抑郁症的 3 期研究和针对患有重度抑郁症的男性和女性的 2B 期研究。虽然 AlloP 是 GABAA 受体 (GABAAR) 的强效增强剂，但目前尚不清楚 NAS 的抗抑郁作用仅由 GABA 作用介导，最近的数据表明还可能涉及其他机制，包括对细胞应激和炎症途径的影响。我们中心的成员在药物化学和机制研究方面拥有丰富的经验类 AlloP NAS 的影响的基础。在这个 Conte Center 提案中，我们将利用新颖的 NAS 化合物来探测 NAS 的各种分子、突触、网络和行为效应，作为其线索治疗机制和潜力。我们的中心提案是由独特的 NAS 类似物推动的在我们的化学核心中合成，涉及三个互补且相互交织的项目，这些项目将追求三个具体目标。首先，我们将检验 NAS 对一类对象的选择性操作的假设 GABAAR 是小说中对海马电活动、网络功能和行为影响的基础产后抑郁症和重度抑郁症的小鼠品系和小鼠模型。其次，我们要考察的角色非 GABAA 离子通道介导 NAS 的海马和行为效应，重点关注新型 NAS 调节 NMDA 谷氨酸受体和低压激活的钙通道。这些研究将使用独特的光亲和标记方法来阐明 NAS 对 NMDA 受体的作用位点其他目标。其他研究将检验 NAS 类似物对细胞功能、神经网络的影响功能和行为。第三，我们将测试 NAS 参与的细胞内靶标对海马的作用电路和行为，重点关注神经炎症和细胞应激途径的作用。我们的中心具有独特的优势，可以探索抗抑郁药 NAS 从分子到作用位点的过程以及对功能失调回路的影响，以确定潜在的新型精神药物和靶标治疗的发展。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Enantiomer of Allopregnanolone Prevents Pressure-Mediated Retinal Degeneration Via Autophagy.

DOI：
10.3389/fphar.2022.855779
发表时间：
2022
期刊：
Frontiers in pharmacology
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

The herbicide glyphosate inhibits hippocampal long-term potentiation and learning through activation of pro-inflammatory signaling.

除草剂草甘膦通过激活促炎信号传导抑制海马长时程增强和学习。

DOI：
10.21203/rs.3.rs-2883114/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Izumi,Yukitoshi;O'Dell,KazukoA;Zorumski,CharlesF
通讯作者：
Zorumski,CharlesF

Acrylamide inhibits long-term potentiation and learning involving microglia and pro-inflammatory signaling.

DOI：
10.1038/s41598-022-16762-7
发表时间：
2022-07-20
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Izumi, Yukitoshi;Fujii, Chika;O'Dell, Kazuko A.;Zorumski, Charles F.
通讯作者：
Zorumski, Charles F.

Endogenous recapitulation of Alzheimer's disease neuropathology through human 3D direct neuronal reprogramming.

通过人类 3D 直接神经元重编程内源性重现阿尔茨海默病神经病理学。

DOI：
10.1101/2023.05.24.542155
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Sun,Zhao;Kwon,Ji-Sun;Ren,Yudong;Chen,Shawei;Cates,Kitra;Lu,Xinguo;Walker,CourtneyK;Karahan,Hande;Sviben,Sanja;Fitzpatrick,JamesAJ;Valdez,Clarissa;Houlden,Henry;Karch,CelesteM;Bateman,RandallJ;Sato,Chihiro;Mennerick,Stev
通讯作者：
Mennerick,Stev

A unified total synthesis route to 18-trideuterated and/or 19-trideuterated testosterone, androstenedione and progesterone.

18-三氘代和/或19-三氘代睾酮、雄烯二酮和黄体酮的统一全合成路线。