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前的病理过程 并加快大脑衰老和重度抑郁症（MD）的变性。在此，我们提出了kynurenine（Kyn） 途径是炎症与谷氨酸病理学之间关联的中介。 kynurenines是 神经活性分子很容易通过专用转运蛋白从外围进入大脑 位于血脑屏障的大型中性氨基酸转运蛋白（LAT-1）。一旦大脑进入大脑，Kyn是 通过活化的小胶质细胞转化为代谢物，例如喹啉酸（QA）和3-羟基氰尿苷 （3HK）。这些Kyn的下游代谢产物具有强大的兴奋性（QA）和氧化应激（3HK）和 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 表明基本组织的基因鲁氨酸的产生和转移是从外围组织中的 通过免疫激活和衰老等生物学因素增加。临床前数据还表明 通过亮氨酸对LAT-1的竞争封锁（较高的亲和力配体）封锁Kyn涌入大脑 废除啮齿动物免疫激活引起的抑郁样行为。我们在人类的初步数据 表明外围Kyn在大脑中驱动Kyn代谢物，导致基底神经节谷氨酸增加， 局部神经元活性的相干性降低，大脑区域之间的功能连通性降低，并且 抑郁症行为，包括Anhedonia和心理运动放慢。基于这些数据，我们提出了一个6- 一周的挑战范例，其中炎症增加的中年MD患者将随机分为 亮氨酸或赖氨酸（总计n = 75）。与亮氨酸相反，赖氨酸不会抑制Kyn的涌入，因为它使用了 不同的转运蛋白集（阳离子转运蛋白）进入大脑。我们将估计谷氨酸和肌醇 （星形胶质标记）使用磁共振光谱（MRS）；并研究局部大脑的连贯性 使用基底神经节和背额前额叶皮质（DMPFC）区域的活性和功能连通性。 基线，1周和6周的静止状态功能磁共振成像（fMRI）。使用 标准化的仪器，我们将测量Anhedonia和精神运动在抽样时放慢速度 炎症介质和Kyn代谢产物的脑脊液（仅6周）。该研究设计将测试 假设为期6周的亮氨酸挑战将减少谷氨酸和肌醇（AIM 1），改善局部 基底神经节和DMPFC中的活动相干性和功能连通性（AIM 2），并降低Anhedonia 和心理运动放慢（目标3）。如果得到支持，这些目标将暗示Kyn失调作为关键调解人 MD炎症和衰老引起的大脑和行为变化的变化。此外，这个证明 机理建议将在BBB中识别Kyn及其转运蛋白是新药物的关键目标 MD患者的Anhedonia和心理运动减慢的发展，并有可能阻止 神经变性和痴呆。