MiR-182-5p:一种治疗csds诱导小鼠抑郁的新型生物标志物

IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY International Journal of Neuropsychopharmacology Pub Date : 2024-01-01 DOI:10.1093/ijnp/pyad064
Ya-Bin Zheng, Xiao-Ming Sheng, Xiang Jin, Wei Guan
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摘要

背景:抑郁症是一种致残率高的神经精神疾病,主要由慢性应激或遗传因素引起。越来越多的证据表明,mirna在抑郁症的发病机制中起着至关重要的作用。然而,到目前为止,miRNA抑制病理生理的潜在分子机制仍然完全不清楚。方法:首先建立慢性社会失败应激(CSDS)小鼠抑郁模型,通过一系列行为测试评估小鼠的抑郁样行为。接下来,我们检测了几个在以前的报道中被认为参与抑郁的高表达mirna,并发现miR-182-5p被选为海马的候选分析,然后使用western blotting和免疫荧光一起检测AAV-siR-182-5p治疗是否缓解了慢性应激诱导的海马Akt/GSK3β/CREB信号通路的减少以及神经发生损伤和神经炎症的增加。此外,我们采用camp反应元件结合蛋白(CREB)抑制剂来检测阻断Akt/GSK3β/CREB信号通路是否会消除小鼠AAV-siR-182-5p的抗抑郁作用。结果:miR-182-5p敲低可减轻csds诱导小鼠的抑郁样行为和神经发生受损。有趣的是,agomiR-182-5p的使用显著增加了小鼠的静止时间,加重了神经元神经发生损伤。更重要的是,666-15阻断了AAV-siR-182-5p在行为学测试中对csds诱导的抑郁样行为和海马内神经元神经发生的逆转作用。结论:这些发现提示海马miR-182-5p/Akt/GSK3β/CREB信号通路参与了抑郁症的发病机制,临床中基于miRNA靶点的新药开发可能会有更多的机会。
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MiR-182-5p: A Novel Biomarker in the Treatment of Depression in CSDS-Induced Mice.

Background: Depression is a neuropsychiatric disease with a high disability rate and mainly caused by the chronic stress or genetic factors. There is increasing evidence that microRNAs (miRNAs) play a critical role in the pathogenesis of depression. However, the underlying molecular mechanism for the pathophysiology of depression of miRNA remains entirely unclear so far.

Methods: We first established a chronic social defeat stress (CSDS) mice model of depression, and depression-like behaviors of mice were evaluated by a series of behavioral tests. Next, we detected several abundantly expressive miRNAs suggested in previous reports to be involved in depression and found miR-182-5p was selected as a candidate for analysis in the hippocampus. Then western blotting and immunofluorescence were used together to examine whether adeno-associated virus (AAV)-siR-182-5p treatment alleviated chronic stress-induced decrease in hippocampal Akt/GSK3β/cAMP-response element binding protein (CREB) signaling pathway and increase in neurogenesis impairment and neuroinflammation. Furthermore, CREB inhibitor was adopted to examine if blockade of Akt/GSK3β/CREB signaling pathway abolished the antidepressant actions of AAV-siR-182-5p in mice.

Results: Knockdown of miR-182-5p alleviated depression-like behaviors and impaired neurogenesis of CSDS-induced mice. Intriguingly, the usage of agomiR-182-5p produced significant increases in immobility times and aggravated neuronal neurogenesis damage of mice. More importantly, it suggested that 666-15 blocked the reversal effects of AAV-siR-182-5p on the CSDS-induced depressive-like behaviors in behavioral testing and neuronal neurogenesis within hippocampus of mice.

Conclusions: These findings indicated that hippocampal miR-182-5p/Akt/GSK3β/CREB signaling pathway participated in the pathogenesis of depression, and it might give more opportunities for new drug developments based on the miRNA target in the clinic.

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来源期刊
CiteScore
8.40
自引率
2.10%
发文量
230
审稿时长
4-8 weeks
期刊介绍: The central focus of the journal is on research that advances understanding of existing and new neuropsychopharmacological agents including their mode of action and clinical application or provides insights into the biological basis of psychiatric disorders and thereby advances their pharmacological treatment. Such research may derive from the full spectrum of biological and psychological fields of inquiry encompassing classical and novel techniques in neuropsychopharmacology as well as strategies such as neuroimaging, genetics, psychoneuroendocrinology and neuropsychology.
期刊最新文献
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