Novel mechanisms mediating the rapid antidepressant actions of glyoxylase 1 inhibitors

介导乙二醛酶 1 抑制剂快速抗抑郁作用的新机制

基本信息

批准号：
10351962
负责人：
STEPHANIE C DULAWA
金额：
$ 18.59万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10351962
关键词：
AMPA Receptors Acids Agonist Animals Antidepressive Agents Behavior Brain-Derived Neurotrophic Factor Calcium Chronic Clinical Computer Models Data Development Enzymes Fiber Frustration GABA-A Receptor Genetic Glycolysis Habenula Home Hour Human Image Impairment Infusion procedures Ketamine Lateral Mediating Mental Depression Molecular Morbidity - disease rate Motivation Mus Mutation N-Methyl-D-Aspartate Receptors Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Patients Phosphotransferases Photometry Physiological Pyruvaldehyde Rattus Regulation Reporting Rewards Rodent Role Signal Transduction Slice Stress T-Type Calcium Channels Testing Therapeutic Tropomyosin Viral Vector antagonist antidepressant effect awake depressed patient disability forced swim test gamma-Aminobutyric Acid inhibitor novel novel therapeutics prevent receptor release factor response side effect suicidal risk virtual voltage

项目摘要

PROJECT SUMMARY Depression is the leading cause of disability worldwide. The N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine is the only agent approved for clinical use that induces antidepressant effects within hours to days. However, ketamine treatment is not effective in all patients, and induces problematic side effects. Novel rapid-acting antidepressant agents are greatly needed. We recently found that glyoxylase 1 (GLO1) inhibitors induce rapid-onset antidepressant effects in mice. GLO1 is a ubiquitous cellular enzyme that detoxifies methylglyoxal (MG), a non-enzymatic byproduct of glycolysis. Thus, GLO1 inhibitor treatment increases physiological levels of MG. MG is a competitive partial agonist at GABA-A receptors, and also directly activate tropomyosin receptor kinase B (TrkB), the receptor for brain derived neurotrophic factor (BDNF). Ketamine, and agents inducing rapid-onset antidepressant effects in rodents, trigger activity- dependent BDNF release leading to TrkB activation; this action is required for their rapid-onset antidepressant effects. This proposal aims to identify the molecular and circuit mechanisms that underlie GLO1 inhibitor- induced rapid onset antidepressant effects. We found that GLO1 inhibitor treatment induces antidepressant effects within 24 hours through mechanisms that are largely distinct from those of ketamine. For example, ketamine and other rapid-acting agents induce activation of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which triggers activity-dependent BDNF release and cortical γ oscillations. Surprisingly, we found that GLO1 inhibitor treatment does not induce γ oscillations, and thus likely does not induce AMPA activation or activity-dependent BDNF release. In Aim 1, we will test the hypothesis that GLO1 inhibitor treatment leads to TrkB activation by increasing levels of MG, thus “substituting” for BDNF release. We predict that mice carrying the Val66Met mutation in BDNF, which prevents activity-dependent BDNF release, will show rapid-onset antidepressant responses to GLO1 inhibitors, but not ketamine. We will also test the hypothesis that activation of TrkB receptors within the mPFC is sufficient for GLO1-inhibitor-mediated rapid antidepressant effects. Overactivity of the lateral habenula (LHb) produces depression-like behaviors, and reducing this overactivity has antidepressant effects. Our calcium imaging findings show that application of either MG or ketamine to LHb slices from congenitally helpless rats reduces LHb neuronal overactivity. While ketamine mediates this effect by blocking NMDARs and low-voltage-sensitive T-type calcium channels, we predict that GLO1 inhibitors produce this effect by activating GABA-ARs via MG. In Aim 2, we will test the hypothesis that activation of LHb GABA-ARs is sufficient to mediate GLO1-mediated rapid-onset antidepressant effects. Lastly, we will use multispectral photometry to test the hypothesis that GLO1 inhibitor-mediated inhibition of an mPFC- LHb projection is sufficient to induce rapid-onset antidepressant effects. Identifying novel mechanisms of rapid- onset antidepressant effects is essential for developing new therapeutics.

项目摘要抑郁症是全球残疾的主要原因。 N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂氯胺酮是唯一批准诱导抗抑郁药的药物在几个小时到几天之内产生影响。但是，氯胺酮治疗在所有患者中均不有效，并且会影响问题的副作用。非常需要新型的快速作用抗抑郁药。我们最近发现糖基酶1（GLO1）抑制剂在小鼠中诱导快速发作的抗抑郁作用。 GLO1是无处不在的细胞糖化甲基乙二醇（Mg）的甲基乙二醇（MG）的酶，这是糖酵解的非酶副产品。那是GLO1抑制剂治疗增加了MG的物理水平。 MG是GABA-A受体的竞争性部分激动剂，并且还直接激活tropomyosin受体激酶B（TRKB），这是脑衍生神经营养因子的受体（bdnf）。氯胺酮和药物在啮齿动物中诱导快速发作的抗抑郁作用，触发活性 - 依赖性BDNF释放导致TRKB激活；它们的快速发作抗抑郁药需要此操作效果。该建议旨在确定GLO1抑制剂基础的分子和电路机制诱导快速发作抗抑郁作用。我们发现GLO1抑制剂治疗诱导抗抑郁药在24小时内通过与氯胺酮不同的机制作用。例如，氯胺酮和其他迅速作用的药物会诱导A-Amino-3-羟基-5-甲基-4-异沙唑股东的激活酸（AMPA）接收器，这会触发活性依赖性的BDNF释放和皮质γ振荡。出奇，我们发现GLO1抑制剂治疗不会诱导γ振荡，因此可能不会诱导AMPA 激活或活动依赖性BDNF释放。在AIM 1中，我们将测试GLO1抑制剂的假设治疗通过增加Mg水平而导致TRKB激活，从而“代替” BDNF释放。我们预测携带val66met突变在BDNF中的小鼠将显示与活动相关的BDNF释放，将显示对GLO1抑制剂的快速抗抑郁反应，而不是氯胺酮。我们还将检验假设 MPFC中TRKB受体的激活足以用于GLO1抑制剂介导的快速抗抑郁药效果。外侧Habenula（LHB）的过度活动性产生抑郁症的行为，并减少过度活动具有抗抑郁作用。我们的钙成像发现表明，使用mg或先天无助的大鼠的氯胺酮到LHB切片可降低LHB神经元过度活跃。而氯胺酮通过阻断NMDAR和低压敏感的T型钙通道来介导这种效果，我们预测 GLO1抑制剂通过MG激活GABA-ARS产生了这种效果。在AIM 2中，我们将检验以下假设。 LHB GABA-AR的激活足以介导GLO1介导的快速发作抗抑郁作用。最后，我们将使用多光谱光度法来测试GLO1抑制剂介导的MPFC-的抑制作用的假设 LHB投影足以诱导快速发作的抗抑郁作用。确定快速的新机制发作抗抑郁作用对于开发新疗法至关重要。