Kynurenine Pathway in the Pathogenesis of Post-Stroke Depression in aged Mice

犬尿氨酸通路在老年小鼠中风后抑郁症发病机制中的作用

• 批准号: 10490405
• 负责人: Antonio Lucio Teixeira
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490405
• 关键词: Address; Adult; Affect; Aging; Agonist; Animal Genetics; Animal Model; Animals; Attenuated; Behavior; Behavior Control; Behavior Disorders; Behavioral; Brain; Catabolism; Cells; Cerebrum; Cytotoxic T-Lymphocytes; Depressive disorder; Development; Dioxygenases; Elderly; Encephalitis; Enzymes; Equilibrium; Essential Amino Acids; Exhibits; Female; Flow Cytometry; Future; Generations; Goals; Helper-Inducer T-Lymphocyte; Hour; Human; Immune; Immunohistochemistry; Infarction; Inflammaging; Inflammation; Inflammatory; Knockout Mice; Kynurenic Acid; Kynurenine; Kynurenine 3-monooxygenase; Kynurenine-oxoglutarate aminotransferase; Lead; Left; Leukocytes; Mass Spectrum Analysis; Measurement; Measures; Mental Depression; Mental disorders; Metabolism; Microglia; Middle Cerebral Artery Occlusion; Modeling; Motor; Mus; N-Methyl-D-Aspartate Receptors; Neuraxis; Neurons; Neutrophil Infiltration; Pathogenesis; Pathway interactions; Patients; Peripheral; Pharmacology; Phenotype; Plasma; Population; Prevention; Production; Quality of life; Quinolinic Acid; Reactive Oxygen Species; Recovery; Recovery of Function; Residual state; Role; Sensory; Series; Serotonin; Stress; Stroke; Therapeutic; Tissues; Translations; Tryptophan; Tryptophan 2,3 Dioxygenase; United States; Western Blotting; Wild Type Mouse; Woman; aged; aging brain; artery occlusion; behavior test; biological systems; cohort; cytokine; depressive symptoms; design; disability; enzyme pathway; excitotoxicity; forced swim test; functional disability; high risk; improved; inhibitor; macrophage; male; monocyte; nervous system disorder; neurological recovery; neuroprotection; neurotoxic; neurotoxicity; new therapeutic target; older patient; physically handicapped; post stroke; post stroke depression; prevent; sex; sham surgery; stroke patient; stroke survivor; systemic inflammatory response; targeted treatment; therapeutic development; therapeutic target; therapeutically effective; therapy development; translational potential

Project Summary Aging is metabolism modifiable Post-stroke depression (PSD) affects over 40% of patients and negatively influences their recovery. The kynurenine pathway (KP) is the main catabolic pathway of tryptophan, the precursor of serotonin, and has been independently implicated in both depression and stroke. The KP has never been evaluated in the context of PSD, and is a very promising pathway for development of therapeutic targets. In our preliminary studies, we have found that aged mice, but not young mice, develop a significant PSD phenotype. Moreover, compared to the young brain, the brain levels of a key enzyme in the KP, kynurenine 3-monooxygenase (KMO), are higher in the aged brain at baseline, and increase after stroke. Our main hypothesis is that inhibiting KMO activity will prevent and/or minimize the development of PSD in aged animals, and that this will produce a more robust effect in aged females. To address our first aim, i.e. determine whether the post-stroke increase in KMO expression and KP metabolites varies according to sex, we will measure KMO expression and KP metabolites in the brain and plasma of aged mice subjected to reversible middle cerebral arterial occlusion (MCAO). In aim 2, i.e. to determine whether KMO inhibition prevents PSD, reduces inflammation, and improves recovery, aged animals from both sexes will be subjected to stroke or sham surgery, and half of the animals will be treated with Ro 61- 8048, a KMO inhibitor, and the other half with vehicle. A series of behavioral tests will be performed to evaluate neurological recovery and PSD phenotypes. We will then use KMO knockout mice to further validate our hypothesis, assessing how deletion of KMO will alter infarct size, PSD phenotypes and recovery in both aged males associated with in multiple biological systems, including altered and increased brain and systemic inflammation, also known as `inflammaging'. Aging is a non- risk factor for many neurological diseases, including stroke. significant changes serotonin and females. The results obtained in this project will determine contribute the mechanisms by which aging and KP to the pathogenesis of PSD. Furthermore, this contribution is expected to have high translational potential, constituting the theoretical framework for developing future trials in humans.

项目摘要 老化 是 代谢 可修改后击球后抑郁症（PSD）影响 超过40％的患者和负面影响他们的康复。 Kynurenine途径（KP）是主要的 色氨酸的分解代谢途径（5-羟色胺的前体），并已独立涉及两者 抑郁和中风。 KP从未在PSD的背景下进行评估，这是一个非常有前途的 开发治疗靶标的途径。在我们的初步研究中，我们发现了老年小鼠，但是 不是小鼠，会发展出重要的PSD表型。而且，与年轻的大脑相比，大脑水平 KP中的关键酶，kynurenine 3-偶加酶（KMO）在基线时老化的大脑中较高，并且 中风后增加。我们的主要假设是抑制KMO活性将预防和/或最小化 老年动物中PSD的发展，这将在老年女性中产生更强大的效果。 为了解决我们的第一个目标，即确定势后kmo表达和KP的增加是否增加 代谢产物根据性别而变化，我们将测量大脑中的KMO表达和KP代谢产物 衰老小鼠的血浆受到可逆的脑动脉闭塞（MCAO）。在AIM 2中，即 确定KMO抑制是否防止PSD，减少炎症并改善恢复，年龄的动物 两性都将接受中风或假手术，一半的动物将用RO 61-进行治疗 8048，一个KMO抑制剂，另一半带有车辆。将进行一系列行为测试以评估 神经恢复和PSD表型。然后，我们将使用KMO淘汰小鼠进一步验证我们的 假设，评估KMO的缺失将如何改变老年男性的梗塞大小，PSD表型和恢复 与多个生物系统相关联，包括改变 并增加了大脑和全身性炎症，也称为“炎症”。衰老是一个非 许多神经系统疾病的危险因素，包括中风。 5-羟色胺的重大变化 和女性。该项目中获得的结果将确定 贡献 衰老和KP的机制 致PSD的发病机理。此外，这项贡献有望具有很高的翻译 潜在的，构成了发展人类未来试验的理论框架。

项目成果

Further Evidence of Peripheral Inflammatory Markers Involvement in Late-Onset Depression and Cognitive Decline.

• DOI: 10.1016/j.jagp.2021.12.003
• 发表时间: 2021-12
• 期刊: The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry
• 作者: A. L. Teixeira;J. Dumas

The Involvement of Kynurenine Pathway in Neurodegenerative Diseases.

• DOI: 10.2174/1570159x20666220922153221
• 发表时间: 2023
• 期刊: Current neuropharmacology
• 影响因子: 5.3