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：
10557209
负责人：
STEPHANIE C DULAWA
金额：
$ 22.18万
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/10557209
关键词：
Acids Agonist Animals Antidepressive Agents Behavior Brain-Derived Neurotrophic Factor Calcium Chronic Clinical Computer Models Data Development Drug Metabolic Detoxication 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 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世界残疾的主要原因。受体（NMDAR）拮抗剂氯胺酮是唯一被批准用于临床的抗抑郁药物然而，氯胺酮治疗并非对所有患者都有效，并且会导致副作用。我们最近发现，急需新型速效抗抑郁药。乙二醛酶 1 (GLO1) 抑制剂可在小鼠中诱导快速起效的抗抑郁作用。解毒甲基乙二醛 (MG) 的酶，甲基乙二醛是糖酵解的非酶副产物，因此是 GLO1 抑制剂。治疗可增加 MG 的生理水平 MG 是 GABA-A 受体的竞争性部分激动剂，并且还直接激活原肌球蛋白受体激酶 B (TrkB)，即脑源性神经营养因子的受体（BDNF），以及在啮齿动物中诱导快速起效的抗抑郁作用的药物，触发活性- 依赖性 BDNF 释放导致 TrkB 激活；这种作用是其快速起效的抗抑郁药所必需的该提案旨在确定 GLO1 抑制剂的分子和电路机制。诱导快速起效的抗抑郁作用我们发现 GLO1 抑制剂治疗可诱导抗抑郁作用。 24 小时内通过与氯胺酮截然不同的机制发挥作用。氯胺酮和其他速效药物可诱导α-氨基-3-羟基-5-甲基-4-异恶唑丙酸的活化酸 (AMPA) 受体，触发活性依赖性 BDNF 释放和皮质 γ 振荡。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 在目标 1 中，我们将检验 GLO1 抑制剂的假设。我们预测，治疗会通过增加 MG 水平来激活 TrkB，从而“替代”BDNF 的释放。 BDNF 中携带 Val66Met 突变的小鼠将表现出，这种突变会阻止活性依赖性 BDNF 的释放对 GLO1 抑制剂（而非氯胺酮）的快速起效抗抑郁反应我们还将检验这一假设。 mPFC 内 TrkB 受体的激活足以实现 GLO1 抑制剂介导的快速抗抑郁药外侧缰核 (LHb) 的过度活动会产生抑郁样行为，并减少这种行为。我们的钙成像研究结果表明，使用 MG 或 MG 具有抗抑郁作用。氯胺酮对先天无助的大鼠的 LHb 切片可减少 LHb 神经元过度活跃。通过阻断 NMDAR 和低电压敏感 T 型钙通道介导这种效应，我们预测 GLO1 抑制剂通过 MG 激活 GABA-AR 来产生这种效果。在目标 2 中，我们将检验以下假设： LHb GABA-AR 的激活足以介导 GLO1 介导的快速起效的抗抑郁作用。我们将使用多光谱光度测定来检验 GLO1 抑制剂介导的 mPFC 抑制作用的假设 LHb 预测足以诱导快速起效的抗抑郁作用。发挥抗抑郁作用对于开发新疗法至关重要。