Investigating the Role of TNF-Alpha through Blood-Brain Barrier Integrity in Stress-Induced Depression.

Q3 Pharmacology, Toxicology and Pharmaceutics
Neuropsychopharmacologia Hungarica Pub Date : 2024-12-01
Tamas Nagy, Daniel Baksa, Peter Petschner, Xenia Gonda, Zsofia Gal, Gabriella Juhasz, Gyorgy Bagdy
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引用次数: 0

Abstract

Background: Major depressive disorder (MDD) is a complex psychiatric condition significantly impacted by environmental stress and inflammation. Previous research suggests that stress-induced alterations in the blood-brain barrier (BBB) may allow pro-inflammatory cytokines like interleukin-6 (IL-6) to enter the brain, contributing to depression. Tumor necrosis factor-alpha (TNF-α) is another prominent cytokine implicated in depression, but its role in the context of BBB integrity and stress-mediated depression remains unclear.

Objectives: This study aimed to investigate whether TNF-α plays a similar role as IL-6 in the development of depression through interactions with environmental stress and BBB integrity. Specifically, we examined the interaction between environmental stress, genetic variants of CLDN5 (the gene of the Claudin-5, a protein critical for BBB integrity), and TNF (the gene encoding the TNF-α protein) genetic variants on depressive symptoms.

Methods: We utilized data from the UK Biobank, comprising genetic, health, and lifestyle information from approximately 500,000 participants aged 40 to 69. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9) and a composite Current Depressive Symptoms (CDS) score based on self-reported questionnaire items. Environmental stress was quantified through participants' reports of significant life events in the past two years. Genetic analysis focused on 15 single nucleotide polymorphisms (SNPs) within the TNF gene (after linkage disequilibrium pruning) and a functional polymorphism in CLDN5 (rs885985). Linear regression models were used to assess main effects, gene-gene interactions, gene-environment interactions, and three-way interactions on depressive symptoms, adjusting for covariates and applying Bonferroni correction for multiple testing.

Results: No significant associations were found between TNF genetic variants and depressive symptoms after correcting for multiple testing. While some TNF SNPs showed nominal significance in interaction models - most notably rs3093546, which showed nominal significance in both depressive phenotypes - the findings were not robust enough to confirm a significant role. Unlike previous findings with IL6, TNF did not exhibit significant interactions with environmental stress and CLDN5 variants affecting depression risk.

Conclusions: The study does not support a significant role for TNF genetic variants interacting with environmental stress and BBB integrity in influencing depression risk. These findings suggest that IL-6 and BBB integrity may be more critical targets for understanding and treating stress-related depression, highlighting the complexity of depression's pathophysiology.

(Neuropsychopharmacol Hung 2024; 26(4): 197-203)

研究tnf - α通过血脑屏障完整性在应激性抑郁症中的作用。
背景:重度抑郁障碍(MDD)是一种复杂的精神疾病,受环境应激和炎症的显著影响。先前的研究表明,压力引起的血脑屏障(BBB)的改变可能允许像白细胞介素-6 (IL-6)这样的促炎细胞因子进入大脑,从而导致抑郁症。肿瘤坏死因子-α (TNF-α)是另一个与抑郁症有关的重要细胞因子,但其在血脑屏障完整性和应激介导的抑郁症中的作用尚不清楚。目的:本研究旨在探讨TNF-α是否通过与环境应激和血脑屏障完整性的相互作用在抑郁症的发展中发挥与IL-6相似的作用。具体来说,我们研究了环境压力、CLDN5 (CLDN5的基因,一种对血脑屏障完整性至关重要的蛋白质)的遗传变异和TNF(编码TNF-α蛋白的基因)的遗传变异在抑郁症状中的相互作用。方法:我们利用来自英国生物银行的数据,包括来自大约50万名年龄在40至69岁之间的参与者的遗传、健康和生活方式信息。采用患者健康问卷-9 (PHQ-9)和基于自述问卷项目的当前抑郁症状(CDS)综合评分对抑郁症状进行评估。环境压力是通过参与者对过去两年重大生活事件的报告来量化的。遗传分析集中在TNF基因内的15个单核苷酸多态性(snp)(连锁不平衡修剪后)和CLDN5 (rs885985)的功能多态性。采用线性回归模型评估主效应、基因-基因相互作用、基因-环境相互作用和三方相互作用对抑郁症状的影响,对协变量进行调整,并对多重检验采用Bonferroni校正。结果:经多次检测校正后,TNF基因变异与抑郁症状之间未发现显著关联。虽然一些TNF snp在相互作用模型中显示出名义上的显著性——最值得注意的是rs3093546,它在两种抑郁表型中都显示出名义上的显著性——但研究结果不足以证实其显著作用。与之前对il - 6的研究结果不同,TNF与环境应激和影响抑郁风险的CLDN5变异之间没有明显的相互作用。结论:该研究不支持TNF基因变异与环境应激和血脑屏障完整性相互作用在影响抑郁风险中的重要作用。这些发现表明,IL-6和血脑屏障完整性可能是理解和治疗压力相关性抑郁症的更关键的靶点,突出了抑郁症病理生理的复杂性。(神经精神药物,洪2024;26 (4): 197 - 203)
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neuropsychopharmacologia Hungarica
Neuropsychopharmacologia Hungarica Medicine-Medicine (all)
CiteScore
1.60
自引率
0.00%
发文量
8
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