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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结：慢性炎症和谷氨酸失调是发病前的病理过程