Hochman Eldar, Taler Michal, Flug Reut, Gur Shay, Dar Shira, Bormant Gil, Blattberg Dori, Nitzan Uri, Krivoy Amir, Weizman Abraham
Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel; Geha Mental Health Center, Petah-Tikva, Israel; Laboratory of Molecular and Biological Psychiatry, Felsenstein Medical Research Center, Petah-Tikva, Israel.
Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel; The Pediatric Molecular Psychiatry Laboratory, Sheba Tel Hashomer Medical Center, Ramat Gan, Israel.
Brain Behav Immun. 2023 Mar;109:162-167. doi: 10.1016/j.bbi.2023.01.015. Epub 2023 Jan 24.
Accumulating evidence indicates that inflammation and neurovascular unit (NVU) dysfunction contribute to depression via disrupted blood-brain barrier (BBB) integrity. Claudin-5, an endothelial tight-junction protein expressed in the NVU and contributing to BBB integrity, has been implicated in psychiatric disorders, including major depressive disorder (MDD) and schizophrenia. In an animal model of depressive-like behavior, the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) was found to affect BBB permeability and claudin-5 expression of NVU endothelial cells. To the best of the authors' knowledge, this study is the first to assess the relationship between serum claudin-5 and TNF-α levels, during major depressive episodes (MDEs). Serum levels of claudin-5 and TNF-α of 40 patients diagnosed with current MDE [19 with MDD and 21 with bipolar disorder (BD)] and 28 matched healthy controls (HCs) were analyzed. Claudin-5 and TNF-α serum levels in the MDE group were significantly higher than in the HC one. Discrete analysis according to MDE type indicated significantly increased claudin-5 serum levels in BD but not in MDD patients, compared to HCs, even after controlling for confounders. In the MDE group, a significant positive correlation was found between claudin-5 and TNF-α serum levels. In complementary analysis, serum levels of the pro-inflammatory cytokine interleukin-6 were significantly higher among MDE patients compared to HCs, however, no significant correlation was found with claudin-5 levels. In conclusion, as indicated by preclinical studies, our clinical study suggests a possible specific interaction between the NVU/BBB marker claudin-5 and the inflammatory marker TNF-α in the pathogenesis of depression.
越来越多的证据表明，炎症和神经血管单元（NVU）功能障碍通过破坏血脑屏障（BBB）的完整性导致抑郁症。Claudin-5是一种在内皮紧密连接中表达的蛋白质，存在于NVU中，对BBB的完整性有重要作用，它与包括重度抑郁症（MDD）和精神分裂症在内的精神疾病有关。在一个类似抑郁行为的动物模型中，发现促炎细胞因子肿瘤坏死因子-α（TNF-α）会影响BBB的通透性以及NVU内皮细胞中Claudin-5的表达。据作者所知，本研究首次评估了重度抑郁发作（MDE）期间血清Claudin-5与TNF-α水平之间的关系。分析了40例被诊断为当前MDE的患者（19例MDD患者和21例双相情感障碍（BD）患者）以及28例匹配的健康对照（HC）的血清Claudin-5和TNF-α水平。MDE组的Claudin-5和TNF-α血清水平显著高于HC组。根据MDE类型进行的离散分析表明，与HC相比，即使在控制了混杂因素后，BD患者的Claudin-5血清水平仍显著升高，而MDD患者则不然。在MDE组中，发现Claudin-5与TNF-α血清水平之间存在显著正相关。在补充分析中，与HC相比，MDE患者中促炎细胞因子白细胞介素-6的血清水平显著更高，然而，与Claudin-5水平未发现显著相关性。总之，正如临床前研究所表明的，我们的临床研究表明，在抑郁症的发病机制中，NVU/BBB标志物Claudin-5与炎症标志物TNF-α之间可能存在特定的相互作用。
