Heresco-Levy Uriel, Haviv Jacob, Caine Yehezkel G, Bao Jimmy, Huang Tai-Yu, Shen Chien-Chang, Bogot Naama R
Herzog Medical Center, Jerusalem, Israel.
Psychiatry Department, Hadassah Medical School, Hebrew University, Jerusalem, Israel.
Front Pharmacol. 2025 May 30;16:1554337. doi: 10.3389/fphar.2025.1554337. eCollection 2025.
Both chronic obstructive pulmonary disease (COPD) and depression are associated with chronic inflammation and their comorbidity represents a critical unmet treatment need. N-methyl-D-aspartate glutamatergic receptors (NMDAR) are well characterized in CNS and widely expressed in lung tissue and inflammation-related cells. Pathologic NMDAR activation, leading to proinflammatory signaling, reactive oxidative stress and tissue damage plays a crucial role in chronic lung injury and depression. D-cycloserine (DCS), an antitubercular antibiotic, acts also as a NMDAR functional antagonist and has antidepressant and anti-inflammatory effects. We hypothesize that NMDAR downregulation represents a unified molecular target for the treatment of COPD-depression comorbidity. This study assessed whether DCS can ameliorate lung injury and depression-like behavior in the porcine pancreatic elastase (PPE)/ lipopolysaccharide (LPS) murine COPD model.
Male BALB/c mice 7-8 weeks old received PPE intratracheally (IT) (1.2 U/20 µL/mouse) on days 0, 7, 14 and 21 and LPS (7 µg/20 µL/mouse) on days 4, 11, 18 and 25 (Groups 2-5). Sham control mice (Group 1) received same volume of saline IT in the same schedule as PPE and LPS. Vehicle (saline) or DCS 100 or 200 mg/kg were administered intraperitoneally once daily from day 28 to day 34 (Groups 2-4). An additional group (Group 5) received DCS 100 mg/kg once weekly (days 7, 14 and 21) and once daily from day 28 to day 34. On day 35 mice underwent the forced swim test (FST) and lungs were harvested for histopathological analyses.
Inflammatory cell infiltration, focal emphysema, measured by the mean linear intercept (MLI), and FST immobility duration, a rodent proxy for depression, were all increased (p < 0.05) in the vehicle group. In comparison with the vehicle group, immobility duration was reduced (p < 0.05) in both DCS 100 mg/kg groups. Moreover, the severity grading of lung inflammation and MLI were reduced (p < 0.05) in the DCS 100 mg/kg × 10 group and in all DCS-treated groups, respectively.
Our findings suggest beneficial DCS effects and warrant further DCS investigation as an innovative treatment for COPD-depression comorbidity.
慢性阻塞性肺疾病（COPD）和抑郁症均与慢性炎症相关，二者并存代表了一种亟待满足的关键治疗需求。N-甲基-D-天冬氨酸谷氨酸能受体（NMDAR）在中枢神经系统中已得到充分表征，并在肺组织和炎症相关细胞中广泛表达。病理性NMDAR激活导致促炎信号传导、活性氧化应激和组织损伤，在慢性肺损伤和抑郁症中起关键作用。D-环丝氨酸（DCS）是一种抗结核抗生素，也作为NMDAR功能拮抗剂发挥作用，具有抗抑郁和抗炎作用。我们假设NMDAR下调是治疗COPD-抑郁症并存的统一分子靶点。本研究评估了DCS是否能改善猪胰弹性蛋白酶（PPE）/脂多糖（LPS）诱导的小鼠COPD模型中的肺损伤和抑郁样行为。
7-8周龄雄性BALB/c小鼠在第0、7、14和21天经气管内（IT）给予PPE（1.2 U/20 μL/小鼠），并在第4、11、18和25天给予LPS（7 μg/20 μL/小鼠）（第2-5组）。假手术对照小鼠（第1组）按照与PPE和LPS相同的时间表接受相同体积的生理盐水IT注射。从第28天至第34天，每天腹腔注射一次溶媒（生理盐水）或100或200 mg/kg的DCS（第2-4组）。另一组（第5组）在第7、14和21天每周一次给予100 mg/kg的DCS，并从第28天至第34天每天一次。在第35天，小鼠接受强迫游泳试验（FST），并采集肺组织进行组织病理学分析。
溶媒组的炎症细胞浸润、通过平均线性截距（MLI）测量的局灶性肺气肿以及FST不动时间（啮齿动物抑郁症的替代指标）均增加（p < 0.05）。与溶媒组相比，两个100 mg/kg DCS组的不动时间均减少（p < 0.05）。此外，100 mg/kg×10 DCS组和所有DCS治疗组的肺部炎症严重程度分级和MLI分别降低（p < 0.05）。
我们的研究结果表明DCS具有有益作用，有必要进一步研究DCS作为COPD-抑郁症并存的创新治疗方法。
