Leucine as a Probe of Kynurenine-Induced Glutamate and Neural Circuit Dysfunction in Midlife Depression

亮氨酸作为犬尿氨酸诱导的谷氨酸和中年抑郁症神经回路功能障碍的探针

• 批准号: 10753154
• 负责人: Ebrahim Haroon
• 金额: $ 68.77万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-17 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753154
• 关键词: Affinity; Aging; Agonist; Amino Acid Transport System L; Amino Acids; Anhedonia; Astrocytes; Basal Ganglia; Behavior; Behavior assessment; Behavioral; Bilateral; Biological Factors; Blood - brain barrier anatomy; Blood specimen; Body mass index; Brain; Brain region; C-reactive protein; Caring; Cerebrospinal Fluid; Chronic; Cognitive; Corpus striatum structure; Data; Dedications; Dementia; Distress; Dose; Double-Blind Method; Early Intervention; Elderly; Endotoxins; Enzymes; Equilibrium; Equipment and supply inventories; Excitatory Neurotoxins; Expenditure; Fiber; Functional Magnetic Resonance Imaging; Functional disorder; Glutamates; Goals; Herpes Labialis; Human; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inositol; Knowledge; Kynurenic Acid; Kynurenine; Leucine; Ligands; Lysine; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Measures; Mediator; Mental Depression; Metabolism; Microglia; N-Methylaspartate; Nature; Nerve Degeneration; Neuronal Dysfunction; Neurons; Outcome; Oxidative Stress; Oxygen; Pathologic Processes; Pathology; Pathway interactions; Patient Self-Report; Patients; Peripheral; Pharmaceutical Preparations; Plasma; Pre-Clinical Model; Prefrontal Cortex; Procedures; Production; Proxy; Publishing; Quinolinic Acid; Randomized; Research Design; Rest; Rewards; Rodent; Safety; Sampling; Source; Standardization; Suicide; Testing; Time; Tissues; Toxic effect; Translating; Treatment outcome; Tryptophan 2,3 Dioxygenase; aged; aging brain; antagonist; arm; brain dysfunction; cognitive testing; cytokine; depressed patient; depressive behavior; depressive symptoms; design; disability; drug development; excitotoxicity; frailty; functional MRI scan; human old age (65+); immune activation; improved; indexing; inflammatory milieu; instrument; middle age; neural circuit; neurocognitive test; neuron loss; new therapeutic target; novel; peripheral blood; pleasure; power analysis; pre-clinical; preclinical study; prevent; primary outcome; prospective; recruit; secondary outcome; targeted agent; transmission process; treatment response

Project Summary: Chronic inflammation and glutamate dysregulation are pathological processes that precede and hasten brain aging and degeneration in major depression (MD). Herein, we propose the kynurenine (KYN) pathway as a mediator of the association between inflammation and glutamate pathologies. Kynurenines are neuroactive molecules that readily access the brain from the periphery via dedicated transporters known as large neutral amino acid transporters (LAT-1) located in the blood-brain barrier. Once inside the brain, KYN is converted by activated microglial cells into metabolites such as quinolinic acid (QA) and 3-hydroxykynurenine (3HK). These downstream metabolites of KYN exert robust excitotoxicity (QA) and oxidative stress (3HK) and ultimately can lead to neuronal dysfunction and death. Extensive preclinical data and our preliminary data indicate that the production and transfer of kynurenines into the brain from peripheral tissues is substantially increased by biological factors such as immune activation and aging. Preclinical data also indicate that blockade of KYN influx into the brain via competitive blockade of LAT-1 by leucine (a higher affinity ligand) abrogates depressive-like behavior induced by immune activation in rodents. Our preliminary data in humans indicate that peripheral KYN drives KYN metabolites in the brain, leading to increased basal ganglia glutamate, reduced coherence of local neuronal activity, decreased functional connectivity among brain regions, and depressive behaviors, including anhedonia and psychomotor slowing. Based on these data, we propose a 6- week challenge paradigm in which middle-aged MD patients with increased inflammation will be randomized to either leucine or lysine (n= 75 total). In contrast to leucine, lysine does not inhibit the influx of KYN as it uses a different set of transporters (cationic transporters) to access the brain. We will estimate glutamate and inositol (astroglial marker) using magnetic resonance spectroscopy (MRS); and study the coherence of local brain activity and functional connectivity in basal ganglia and dorsomedial prefrontal cortical (dmPFC) regions using resting-state functional magnetic resonance imaging (fMRI) at baseline, 1 and 6-weeks of treatment. Using standardized instruments, we will measure anhedonia and psychomotor slowing while sampling blood and cerebrospinal fluid (6 weeks only) for inflammatory mediators and KYN metabolites. This study design will test the hypotheses that a 6-week leucine challenge will decrease glutamate and inositol (Aim 1), improve local activity coherence and functional connectivity in the basal ganglia and dmPFC (Aim 2), and reduce anhedonia and psychomotor slowing (Aim 3). If supported, these aims will implicate KYN dysregulation as a key mediator of the brain and behavioral changes induced by inflammation and aging in MD. Moreover, this proof-of- mechanism proposal will identify KYN and its transporters in the BBB as key targets for novel drug development for treating anhedonia and psychomotor slowing in MD patients and potentially preventing neurodegeneration and dementia.

项目摘要：慢性炎症和谷氨酸失调是先于疾病发生的病理过程。 并加速重度抑郁症 (MD) 的大脑衰老和退化。在此，我们提出犬尿氨酸（KYN） 途径作为炎症和谷氨酸病理学之间关联的介质。犬尿氨酸是 神经活性分子可以通过专用转运蛋白从外周轻松进入大脑 位于血脑屏障的大型中性氨基酸转运蛋白（LAT-1）。一旦进入大脑，KYN 就会 由活化的小胶质细胞转化为代谢物，例如喹啉酸 (QA) 和 3-羟基犬尿氨酸 （3HK）。 KYN 的这些下游代谢物具有强大的兴奋性毒性 (QA) 和氧化应激 (3HK) 最终可能导致神经元功能障碍和死亡。广泛的临床前数据和我们的初步数据 表明犬尿氨酸的产生和从周围组织转移到大脑中的量基本上是 免疫激活和衰老等生物因素会增加。临床前数据还表明 通过亮氨酸（一种更高亲和力的配体）竞争性阻断 LAT-1，阻断 KYN 流入大脑 消除啮齿类动物由免疫激活引起的抑郁样行为。我们在人类身上的初步数据 表明外周 KYN 驱动大脑中的 KYN 代谢物，导致基底神经节谷氨酸增加， 局部神经元活动的一致性降低，大脑区域之间的功能连接性降低，以及 抑郁行为，包括快感缺失和精神运动减慢。根据这些数据，我们提出了 6- 周挑战范例，其中炎症增加的中年 MD 患者将被随机分配到 亮氨酸或赖氨酸（总共 n= 75）。与亮氨酸相反，赖氨酸不会抑制 KYN 的流入，因为它使用 不同组的转运蛋白（阳离子转运蛋白）进入大脑。我们将估计谷氨酸和肌醇 （星形胶质细胞标记）使用磁共振波谱（MRS）；并研究局部大脑的一致性 基底神经节和背内侧前额皮质 (dmPFC) 区域的活动和功能连接 基线、治疗 1 周和 6 周时的静息态功能磁共振成像 (fMRI)。使用 标准化仪器，我们将在采样血液时测量快感缺失和精神运动减慢 脑脊液（仅 6 周）用于检测炎症介质和 KYN 代谢物。本研究设计将测试 假设 6 周的亮氨酸挑战将减少谷氨酸和肌醇（目标 1），改善局部 基底神经节和 dmPFC 的活动一致性和功能连接（目标 2），并减少快感缺失 和精神运动减慢（目标 3）。如果得到支持，这些目标将表明 KYN 失调是关键调解因素 MD 中炎症和衰老引起的大脑和行为变化。此外，这个证明—— 机制提案将确定 KYN 及其在 BBB 中的转运蛋白作为新药的关键靶点 治疗 MD 患者快感缺乏和精神运动减慢并可能预防的开发 神经退行性疾病和痴呆症。