Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, 28 West Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
Department of Physiology and Institute of Neuroscience, Medical College, University of South China, 28 W Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
Neuromolecular Med. 2018 Jun;20(2):252-261. doi: 10.1007/s12017-018-8489-7. Epub 2018 Apr 27.
Our previous works have shown that hydrogen sulfide (HS) significantly attenuates chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and hippocampal endoplasmic reticulum (ER) stress. Brain-derived neurotrophic factor (BDNF) generates an antidepressant-like effect by its receptor tyrosine protein kinase B (TrkB). We have previously found that HS upregulates the expressions of BDNF and p-TrkB in the hippocampus of CUMS-exposed rats. Therefore, the present work was to explore whether BDNF/TrkB pathway mediates the antidepressant-like role of HS by blocking hippocampal ER stress. We found that treatment with K252a (an inhibitor of BDNF/TrkB pathway) significantly increased the immobility time in the forced swim test and tail suspension test and increased the latency to feed in the novelty-suppressed feeding test in the rats cotreated with sodium hydrosulfide (NaHS, a donor of HS) and CUMS. Similarly, K252a reversed the protective effect of NaHS against CUMS-induced hippocampal ER stress, as evidenced by increases in the levels of ER stress-related proteins, glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein and cleaved caspase-12. Taken together, our results suggest that BDNF/TrkB pathway plays an important mediatory role in the antidepressant-like action of HS in CUMS-exposed rats, which is by suppression of hippocampal ER stress. These data provide a novel mechanism underlying the protection of HS against CUMS-induced depressive-like behaviors.
我们之前的工作表明，硫化氢（HS）可显著减轻慢性不可预测轻度应激（CUMS）诱导的抑郁样行为和海马内质网（ER）应激。脑源性神经营养因子（BDNF）通过其受体酪氨酸蛋白激酶 B（TrkB）产生抗抑郁样作用。我们之前发现 HS 可上调 CUMS 暴露大鼠海马中 BDNF 和 p-TrkB 的表达。因此，本工作旨在通过阻断海马 ER 应激来探讨 BDNF/TrkB 通路是否介导 HS 的抗抑郁样作用。我们发现，用 K252a（BDNF/TrkB 通路抑制剂）处理，可显著增加 CUMS 联合 NaHS（HS 的供体）处理大鼠在强迫游泳试验和悬尾试验中的不动时间，并增加新奇抑制性摄食试验中的摄食潜伏期。同样，K252a 逆转了 NaHS 对 CUMS 诱导的海马 ER 应激的保护作用，表现为 ER 应激相关蛋白水平的增加，葡萄糖调节蛋白 78、CCAAT/增强子结合蛋白同源蛋白和裂解的胱天蛋白酶-12。综上所述，我们的结果表明，BDNF/TrkB 通路在 HS 减轻 CUMS 暴露大鼠抑郁样行为中发挥重要的中介作用，其机制是抑制海马 ER 应激。这些数据为 HS 对抗 CUMS 诱导的抑郁样行为提供了一种新的保护机制。
