BDNF-TrkB pathway mediates antidepressant-like roles of H2S in diabetic rats via promoting hippocampal autophagy
BDNF-TrkB pathway mediates antidepressant-like roles of H2S in diabetic rats via promoting hippocampal autophagy
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DOI：
10.1111/1440-1681.13201
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发表时间：
2019-11-24
影响因子：
2.9
通讯作者：
Tang, Xiao-Qing
中科院分区：
文献类型：
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作者：
Liu, Hai-Yao;Wei, Hai-Jun;Tang, Xiao-Qing
硫化氢（H2S）在糖尿病大鼠中起抗抑郁作用。然而，潜在的机制仍不清楚。脑源性神经营养因子（BDNF）是一种神经营养因子，通过其高亲和力的原溶酶相关激酶B （TrkB）受体在抑郁症中发挥重要的调节作用。自噬也与抑郁症的调节有关。先前的研究证实了H2S在BDNF蛋白表达和自噬中的调节作用。因此，在本研究中，我们探讨了BDNF-TrkB通路是否介导H2S在糖尿病大鼠中的抗抑郁样作用，以及该过程是否通过促进海马自噬来实现。我们证明H2S上调链脲佐菌素（STZ）诱导的糖尿病大鼠海马中BDNF和p-TrkB蛋白的表达。K252a （BDNF-TrkB通路的一种抑制剂）逆转了H2S的抗抑郁样作用，这可以通过悬尾、强迫游泳、新奇抑制进食和高水平的+迷宫测试得到证明。此外，K252a可消除h2s促进的糖尿病大鼠海马自噬，表现为自噬酶体数量减少，Beclin-1（自噬体膜形成早期自噬调节因子，其水平与自噬活性正相关）表达下调，P62（自噬降解底物，其水平与自噬活性负相关）表达上调。NaHS和STZ联合治疗大鼠海马的变化。综上所述，这些数据表明BDNF-TrkB通路通过增强海马自噬介导H2S在糖尿病大鼠中的抗抑郁作用。
Hydrogen sulfide (H2S) plays antidepressant-like roles in diabetic rats. However, the underlying mechanisms remain unclear. Brain-derived neurotropic factor (BDNF), a neurotrophic factor, plays important regulatory roles in depression by its high-affinity tropomysin-related kinase B (TrkB) receptor. Autophagy also is implicated in modulation of depression. Previous work confirmed the modulatory roles of H2S in BDNF protein expression and autophagy. Thus, in this study, we explored whether the BDNF-TrkB pathway mediates the antidepressant-like effects of H2S in diabetic rats and whether this process is achieved via promoting hippocampal autophagy. We demonstrated that H2S upregulated the expressions of BDNF and p-TrkB proteins in the hippocampus of streptozotocin (STZ)-induced diabetic rats. K252a (an inhibitor of BDNF-TrkB pathway) reversed the antidepressant-like roles of H2S, as evidenced by the tail suspension, forced swimming, novelty suppressed feeding, and elevated plus-maze tests. Furthermore, K252a abolished H2S-promoted hippocampal autophagy in diabetic rats, as evidenced by a decrease in the number of autolysosome, downregulation of Beclin-1 (a regulator of autophagy in the early stage of the formation of autophagosomal membranes and its level is positively correlated with autophagic activity) expression, and upregulation of P62 (a substrate of autophagic degradation and its level is inversely correlated with autophagic activity) expression, in the hippocampus of rats co-treated with NaHS and STZ. Taken together, these data indicated that the BDNF-TrkB pathway mediates the antidepressant-like roles of H2S in diabetic rats by enhancing hippocampal autophagy.