Abstract：
Typical monoamine-based antidepressants have significant limitations, including a time lag for therapeutic response and low efficacy (more than one-third of depressed patients fail to respond to multiple antidepressant medications and are considered treatment-resistant). Conversely, ketamine, an N-methyl-D-aspartate receptor antagonist, exhibits rapid and sustained antidepressant actions in patients with treatment-resistant depression. However, clinical use of ketamine is limited due to its serious side effects. Thus, there is a significant need to develop novel ketamine-like antidepressants with fewer side effects. We previously demonstrated that intracerebroventricular infusion of resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), specialized pro-resolving lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, produce antidepressant-like effects in mouse models of depression. Among resolvins, RvE1 produces the most potent antidepressant-like effects likely via ChemR23 in several mouse models of depression. Local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) also produces antidepressant-like effects, suggesting that these brain regions are sites of action of RvE1. Additionally, intranasal (i.n.) administration of RvE1 produces antidepressant-like effects through mechanisms similar to ketamine: activity-dependent release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and subsequent mechanistic target of rapamycin complex 1 (mTORC1) activation in the mPFC play a crucial role in the rapid and sustained antidepressant-like actions of i.n. RvE1. Moreover, the antidepressant-like effects of i.n. RvE1 require BDNF and VEGF release, but not mTORC1 activation, in the dorsal DG. These findings suggest that RvE1 can be a promising lead for a novel rapid-acting antidepressant.
摘要：
典型的基于单胺的抗抑郁药有很大的局限性，包括治疗反应的时间滞后和疗效低(超过三分之一的抑郁症患者对多种抗抑郁药无效,被认为是治疗耐药).相反，氯胺酮,一种N-甲基-D-天冬氨酸受体拮抗剂,在难治性抑郁症患者中表现出快速和持续的抗抑郁作用。然而,氯胺酮的临床使用由于其严重的副作用而受到限制。因此，非常需要开发具有较少副作用的新型氯胺酮样抗抑郁药.我们先前证明了脑室内输注消退素（RvD1，RvD2，RvE1，RvE2和RvE3），来自二十二碳六烯酸和二十碳五烯酸的专门的促分解脂质介质，在抑郁症小鼠模型中产生抗抑郁样作用。在解决方法中，RvE1在几种抑郁症小鼠模型中可能通过ChemR23产生最有效的抗抑郁药样作用。局部输注RvE1到内侧前额叶皮质（mPFC）或背海马齿状回（DG）也产生抗抑郁样作用，这表明这些大脑区域是RvE1的作用部位。此外,RvE1的鼻内（i.n.）给药通过类似于氯胺酮的机制产生抗抑郁样作用：脑源性神经营养因子（BDNF）和血管内皮生长因子（VEGF）的活性依赖性释放，mPFC中雷帕霉素复合物1（mTORC1）激活的后续机制靶标在i.n.RvE1的快速和持续的抗抑郁样作用中起着至关重要的作用。此外，i.n.RvE1的抗抑郁样作用需要BDNF和VEGF释放，但不是mTORC1激活，在DG背侧.这些发现表明，RvE1可能是一种新型速效抗抑郁药的有希望的线索。
