Department of Anesthesiology, Seventh Medical Center of PLA General Hospital, 5 Nanmencang Road, Dongcheng, Beijing, 100070, China.
Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian, Beijing, 100850, China.
Neurochem Res. 2020 Aug;45(8):1746-1757. doi: 10.1007/s11064-020-03036-9. Epub 2020 May 7.
Translocator protein 18 kDa (TSPO) is mainly distributed in the outer mitochondrial membrane of steroid-synthesizing cells in the central and peripheral nervous systems. It mediates cholesterol transportation across the phospholipid membrane, which is a prerequisite for neurosteroid synthesis. Though the ligand of TSPO has clinical value in the diagnosis and treatment of neuropsychiatric disorders, the pharmacological study of TSPO for anti-postpartum depression has not been reported. In this study, the classical method of reproductive hormone withdrawal was used to construct a rat model of postpartum depression (PPD). The effect of YL-IPA08, a new ligand compound of TSPO, on PPD was evaluated using multiple behavioral tests at progressive time points. Additionally, real-time quantitative PCR, Western-blotting and an enzyme linked immunosorbent assay were conducted to elucidate the potential molecular mechanism of such effect. We report that the levels of TSPO and neurosteroids in the hippocampus and prefrontal cortex were significantly decreased in PPD rats compared to healthy controls. After 3 weeks of drug treatment, the levels of TSPO and neurosteroids in the hippocampus of PPD rats were increased, and anxiety and depressive like behaviors were alleviated. Meanwhile, compared with sertraline treatment, a positive control in this study, YL-IPA08 treatment had a shorter onset time. Our results suggest that the anxiolytic and anti-depressive activity of YL-IPA08 has significant value in the treatment of PPD and that TSPO may be a potential new target for the treatment of PPD.
转位蛋白 18kDa（TSPO）主要分布在中枢和外周神经系统中合成类固醇的细胞的外线粒体膜上。它介导胆固醇穿过磷脂膜的运输，这是神经甾体合成的前提。虽然 TSPO 的配体在神经精神疾病的诊断和治疗中有临床价值，但 TSPO 用于抗产后抑郁症的药理学研究尚未报道。在这项研究中，使用经典的生殖激素撤退方法构建了产后抑郁症（PPD）大鼠模型。使用多个行为测试在逐步时间点评估 TSPO 的新型配体化合物 YL-IPA08 对 PPD 的影响。此外，进行实时定量 PCR、Western-blotting 和酶联免疫吸附测定以阐明这种作用的潜在分子机制。我们报告 TSPO 和神经甾体在 PPD 大鼠海马体和前额叶皮层中的水平与健康对照组相比显著降低。经过 3 周的药物治疗，PPD 大鼠海马体中的 TSPO 和神经甾体水平增加，焦虑和抑郁样行为得到缓解。同时，与本研究中的阳性对照舍曲林治疗相比，YL-IPA08 治疗的起效时间更短。我们的结果表明，YL-IPA08 的抗焦虑和抗抑郁活性在治疗 PPD 方面具有重要价值，TSPO 可能是治疗 PPD 的潜在新靶点。
