Huang Peng, Wei Songren, Luo Meng, Tang Zhuohong, Lin Qingmei, Wang Xing, Luo Mi, He Yanjun, Wang Chuan, Wei Dezhan, Xia Chenglai, Xu Jiangping
South Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, China.
Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Ann Transl Med. 2021 Oct;9(20):1594. doi: 10.21037/atm-21-5149.
Phosphodiesterase 4D (PDE4D) inhibitor is commonly used to treat depression, but side effects seriously decrease its efficacy. PDE4D was a downstream target mRNA of miR-139-5p. Therefore, we examined the effects of hippocampal miR-139-5p gain- and loss-of-function on depression-like behaviors, the expression level of PDE4D, and hippocampus neurogenesis.
Bioinformatic analyses were carried out to to screen differential genes. Quantitative real-time polymerase chain reaction (qRT-PCR) and luciferase reporter assay were used to confirm the relationship between miR-139-5p and PDE4D. MiR-139-5p mimics, miR-139-5p inhibitor, or miR-NC were used to explore the function of miR-139-5p in HT-22 cells. We further explored the role of miR-139-5p using AAV-injection. Elisa, western blotting, and fluorescence in situ hybridization (FISH) were used to detect the expression of miR-139-5p and PDE4D in CRC tissues.
Here, we showed that PDE4D messenger RNA (mRNA) was a direct target of microRNA (miR)-139-5p, which was downregulated in a chronic ultra-mild stress (CUMS)-induced depression mouse model. Moreover, in experiments , miR-139-5p mimic repressed PDE4D expression in HT-22 cells, but promoted phosphorylated cyclic-AMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) expression. Interestingly, adeno-associated virus (AAV)-miR-139-5p downregulated susceptibility to stress-induced depression-like behaviors in mice. AAV-miR-139-5p suppressed PDE4D in mouse hippocampal cells, increasing expression level of cyclic adenosine monophosphate (cAMP), p-CREB, and BDNF, and stimulating mouse hippocampal neurogenesis.
Our findings suggested that miR-139-5p acted like an antidepressant by targeting PDE4D, thereby regulating the cAMP/protein kinase A (PKA)/CREB/BDNF pathway to improve depression.
磷酸二酯酶4D（PDE4D）抑制剂常用于治疗抑郁症，但副作用严重降低了其疗效。PDE4D是miR-139-5p的下游靶标mRNA。因此，我们研究了海马体中miR-139-5p功能获得和功能缺失对抑郁样行为、PDE4D表达水平以及海马体神经发生的影响。
进行生物信息学分析以筛选差异基因。采用定量实时聚合酶链反应（qRT-PCR）和荧光素酶报告基因检测法来确认miR-139-5p与PDE4D之间的关系。使用miR-139-5p模拟物、miR-139-5p抑制剂或miR-NC来探究miR-139-5p在HT-22细胞中的功能。我们通过腺相关病毒（AAV）注射进一步探究miR-139-5p的作用。采用酶联免疫吸附测定（ELISA）、蛋白质印迹法和荧光原位杂交（FISH）检测结直肠癌组织中miR-139-5p和PDE4D的表达。
在此，我们表明PDE4D信使核糖核酸（mRNA）是微小核糖核酸（miR）-139-5p的直接靶标，在慢性超轻度应激（CUMS）诱导的抑郁小鼠模型中其表达下调。此外，在实验中，miR-139-5p模拟物抑制了HT-22细胞中PDE4D的表达，但促进了磷酸化环磷酸腺苷反应元件结合蛋白（p-CREB）和脑源性神经营养因子（BDNF）的表达。有趣的是，腺相关病毒（AAV）-miR-139-5p降低了小鼠对应激诱导的抑郁样行为的易感性。AAV-miR-139-5p抑制了小鼠海马体细胞中的PDE4D，增加了环磷酸腺苷（cAMP）、p-CREB和BDNF 的表达水平，并刺激了小鼠海马体神经发生。
我们的研究结果表明，miR-139-5p通过靶向PDE4D发挥抗抑郁作用，从而调节cAMP/蛋白激酶A（PKA）/CREB/BDNF通路来改善抑郁症。
