Department of Immunology, School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, China.
Department of Laboratory Medicine, The Second People's Hospital of Guizhou Province, Guiyang, 550004, China.
Curr Med Sci. 2024 Oct;44(5):971-986. doi: 10.1007/s11596-024-2917-8. Epub 2024 Aug 15.
Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are widely expressed in the brain and are associated with the development of neurological and neurodegenerative diseases. However, their roles and molecular mechanisms in major depressive disorder (MDD) remain largely unknown. This study aimed to identify lncRNAs and miRNAs involved in the development of MDD and elucidate their molecular mechanisms.
Transcriptome and bioinformatic analyses were performed to identify miRNAs and lncRNAs related to MDD. C57 mice were subjected to chronic unpredictable mild stress (CUMS) to establish a depression model. Lentiviruses containing either lncRNA NPTN-IT1-201 or miR-142-5p were microinjected into the hippocampal region of these mice. Behavioral tests including the sucrose preference test (SPT), tail suspension test (TST), and forced swim test (FST) were conducted to evaluate depressive-like behaviors.
The results revealed that overexpression of lncRNA NPTN-IT1-201 or inhibition of miR-142-5p significantly ameliorated depressive-like behaviors in CUMS-treated mice. Dual-luciferase reporter assays confirmed interactions between miR-142-5p with both brain-derived neurotrophic factor (BDNF) and NPTN-IT1-201. ELISA analysis revealed significant alterations in relevant biomarkers in the blood samples of MDD patients compared to healthy controls. Histological analyses, including HE and Nissl staining, showed marked structural changes in brain tissues following CUMS treatment, which were partially reversed by lncRNA NPTN-IT1-201 overexpression or miR-142-5p inhibition. Immunofluorescence imaging demonstrated significant differences in the levels of BAX, Bcl2, p65, Iba1 among different treatment groups. TUNEL assays confirmed reduced apoptosis in brain tissues following these interventions. Western blotting showed the significant differences in BDNF, BAX, and Bcl2 protein levels among different treatment groups.
NPTN-IT1-201 regulates inflammation and apoptosis in MDD by targeting BDNF via miR-142-5p, making it a potential therapeutic target for MDD.
长链非编码 RNA（lncRNA）和 microRNA（miRNA）在大脑中广泛表达，与神经和神经退行性疾病的发展有关。然而，它们在重度抑郁症（MDD）中的作用和分子机制在很大程度上仍然未知。本研究旨在鉴定参与 MDD 发展的 lncRNA 和 miRNA，并阐明其分子机制。
进行转录组和生物信息学分析以鉴定与 MDD 相关的 miRNA 和 lncRNA。将 C57 小鼠暴露于慢性不可预测轻度应激（CUMS）下建立抑郁模型。将含有 lncRNA NPTN-IT1-201 或 miR-142-5p 的慢病毒微注射到这些小鼠的海马区。通过蔗糖偏好测试（SPT）、悬尾测试（TST）和强迫游泳测试（FST）进行行为测试，以评估抑郁样行为。
结果表明，lncRNA NPTN-IT1-201 的过表达或 miR-142-5p 的抑制显著改善了 CUMS 处理的小鼠的抑郁样行为。双荧光素酶报告实验证实了 miR-142-5p 与脑源性神经营养因子（BDNF）和 NPTN-IT1-201 之间的相互作用。ELISA 分析显示，与健康对照组相比，MDD 患者的血液样本中的相关生物标志物发生了显著变化。组织学分析，包括 HE 和尼氏染色，显示 CUMS 处理后脑组织发生了明显的结构变化，这些变化部分被 lncRNA NPTN-IT1-201 的过表达或 miR-142-5p 的抑制所逆转。免疫荧光成像显示不同治疗组之间 BAX、Bcl2、p65 和 Iba1 的水平存在显著差异。TUNEL 实验证实这些干预措施后大脑组织中的细胞凋亡减少。Western blot 显示不同治疗组之间 BDNF、BAX 和 Bcl2 蛋白水平存在显著差异。
NPTN-IT1-201 通过靶向 miR-142-5p 调节 BDNF 来调节 MDD 中的炎症和细胞凋亡，使其成为 MDD 的潜在治疗靶点。
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