Department of Psychialogics, Binzhou Municipal Youfu Hospital, Binzhou, Shandong 256600, China.
Comput Math Methods Med. 2022 Aug 28;2022:4244425. doi: 10.1155/2022/4244425. eCollection 2022.
Depression was a common life-threatening psychiatric disorder and occurs more frequently in women than in men. Long noncoding RNAs (lncRNAs), such as LINC00473, had been reported to be involved in the progression of depression.
Chronic unpredictable moderate stress in mice (CUMS) was applied to construct a depression model. Subsequently, RT-qPCR was applied to check the level of LINC00473 and microRNA-497-5p (miR-497-5p) in the hippocampal region of the mice induced by CUMS. CUMS mice were injected with lentiviral vectors of LINC00473 (LV-LINC00473), miR-497-5p inhibitor, short hairpin- (sh-) brain-derived neurotrophic factor (sh-BDNF), or miR-497-5p mimic to evaluate depressive behaviors, including sucrose preference test, forced swim test, elevated plus maze, and tail suspension test. Moreover, the production of hypothalamic neurotransmitters was assessed with the usage of ELISA kits. Dual-luciferase reporter assay, RNA pull-down, and RIP analysis were performed to measure the relationship between miR-497-5p and LINC00473 or BDNF. Further, western blot was employed to determine the protein level of BDNF.
We discovered that LINC00473 level was downregulated in the female mice with depression, but not in male mice. Besides, the depressive behaviors induced by CUMS in mice, including the decrease of sucrose preference and time in open arm, as well as the increase of immobility time and swimming resting time were all ameliorated by LINC00473 overexpression. Moreover, the concentration of neurotransmitters was decreased in CUMS-induced mouse hypothalamus, which was blocked by LV-LINC00473 lentiviral vector administration. Mechanistically, LINC00473 directly targeted miR-497-5p. Absence of miR-497-5p revealed the antidepression effects on CUMS-induced mice, and miR-497-5p upregulation could counter the antidepressive impacts of LINC00473 upregulation on CUMS-induced mice. Furthermore, LINC00473 could target miR-497-5p to modulate BDNF level. Knockdown of BDNF could abrogate the improving influences of miR-497-5p suppression on CUMS-induced depression.
LINC00473 ameliorated CUMS-caused depression by encouraging BDNF expression via binding to miR-497-5p, which might provide a potential therapeutic target for depression in females.
抑郁症是一种常见的危及生命的精神疾病，女性比男性更容易发生。长链非编码 RNA（lncRNA），如 LINC00473，已被报道参与抑郁症的进展。
应用慢性不可预测中度应激（CUMS）构建小鼠抑郁症模型。随后，应用 RT-qPCR 检测 CUMS 诱导的小鼠海马区 LINC00473 和 microRNA-497-5p（miR-497-5p）的水平。用 LINC00473（LV-LINC00473）、miR-497-5p 抑制剂、短发夹 RNA（sh-BDNF）或 miR-497-5p 模拟物注射 CUMS 小鼠，评估包括糖水偏好试验、强迫游泳试验、高架十字迷宫和悬尾试验在内的抑郁行为。此外，使用 ELISA 试剂盒评估下丘脑神经递质的产生。进行双荧光素酶报告基因检测、RNA 下拉和 RIP 分析，以测量 miR-497-5p 与 LINC00473 或 BDNF 之间的关系。进一步采用 Western blot 测定 BDNF 蛋白水平。
我们发现，在患有抑郁症的雌性小鼠中，LINC00473 水平下调，但在雄性小鼠中未下调。此外，CUMS 诱导的小鼠抑郁行为，包括糖水偏好和开放臂时间减少，以及不动时间和游泳休息时间增加，均被 LINC00473 过表达所改善。此外，CUMS 诱导的小鼠下丘脑神经递质浓度降低，LV-LINC00473 慢病毒载体给药可阻断该作用。机制上，LINC00473 可直接靶向 miR-497-5p。miR-497-5p 缺失显示出对 CUMS 诱导的小鼠的抗抑郁作用，而 miR-497-5p 上调可拮抗 LINC00473 过表达对 CUMS 诱导的小鼠的抗抑郁作用。此外，LINC00473 可通过结合 miR-497-5p 来调节 BDNF 水平。BDNF 敲低可消除 miR-497-5p 抑制对 CUMS 诱导的抑郁的改善作用。
LINC00473 通过与 miR-497-5p 结合促进 BDNF 表达，从而改善 CUMS 引起的抑郁，这可能为女性抑郁症提供一个潜在的治疗靶点。
