硫化氢抗抑郁新机制：调控海马坏死性凋亡-神经炎症-犬尿氨酸代谢

在前一个国家自然科学基金(81371485)的资助下，我们开创性地发现硫化氢(H2S)具有确切的抗抑郁作用，且其抗炎作用在其抗抑郁效应中至关重要。基于坏死性凋亡是炎症触发物，而炎症因子诱导的犬尿氨酸代谢紊乱在抑郁发病机制中具有举足轻重的地位，我们认为从调控“海马坏死性凋亡-神经炎症-犬尿氨酸代谢”的视角有望揭示出H2S抗抑郁作用的新机制。为此，我们将在慢性应激性抑郁动物模型上，通过明确H2S依赖于纠正海马犬尿氨酸代谢通路的异常改变而抗抑郁、阐明克服海马坏死性凋亡进而减轻神经炎症反应是H2S纠正海马犬尿氨酸代谢通路的异常改变、最终实现其抗抑郁作用的关键环节，以揭示出“克服海马坏死性凋亡-减轻神经炎症-纠正海马犬尿氨酸代谢紊乱”是H2S抗抑郁作用的重要机制。本项目的开展不仅为确立H2S为防治抑郁症的新途径提供坚实的理论基础；还可阐释出海马坏死性凋亡是抑郁症防治新靶点，为抑郁症的防治提供新思路。

Under the supporting by the previous National Natural Science Foundation of China (81371485), we found that hydrogen sulfide (H2S) has a definite antidepressant-like effect and that the anti-inflammatory action of H2S plays a key role in its antidepressant-like effect. Because necroptosis is a trigger of inflammation and inflammatory factor-induced kynurenine metabolism disorder plays a pivotal role in the pathogenesis of depression, it is expected to reveal novel mechanisms underlying the antidepressant-like effect of H2S from studing the role of regulating hippocampal necroptosis-neuroinflammation-kynurenine metabolism in H2S-exerted antidepressant-like effect. In order to prove the above hypothesis, we will accomplish the following two tasks in the chronic stress-induced depressive animal model: 1) to clear that H2S relies on rectifying the abnormal changes in the kynurenine metabolic pathway in the hippocampus to achieve its antidepressant-like effect; 2) and to clarify that overcoming hippocampal necroptosis, which in turn reducing the neuroinflammatory reaction in hippocampus, is the key component element that H2S rectifies the abnormal changes in the hippocampal kynurenine metabolism pathway, and ultimately to achieve its antidepressant-like effect. Therefore, we will reveal that overcoming hippocampal necroptosis-alleviating neuroinflammation-correcting kynurenine metabolism disorder in hippocampus is an important mechanism underlying the antidepressant-like role of H2S. Carrying out this project will not only provide a solid theoretical basis for establishing H2S as a new way to prevent and treat depression, but also elucidate that the hippocampal necroptosis may be a new target for treatment of depression, providing new thread for the prevention and treatment of depression.