Liu Li, Liu Mei, Zhang Daying, Song Zhiping, Zhang Huaigen
Department of Oncology, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi, P. R. China.
Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P. R. China.
Brain Behav. 2023 Oct;13(10):e3180. doi: 10.1002/brb3.3180. Epub 2023 Aug 7.
Perioperative neurocognitive disorder (PND) is the main cause of poor postoperative recovery in elderly patients with age-related reductions in androgen levels. However, the underlying mechanisms have not been completely elucidated.
A mouse model of PND was constructed using abdominal surgery. Dihydrotestosterone (DHT), as the primary androgen, can improve the cognitive function of mice with PNDs by reducing REDOX damage. To clarify the role of circular RNA (circRNA) in DHT in improving cognitive function in mice with PND, circRNA sequencing was performed to analyze the expression of circRNA in the hippocampus of mice.
We confirmed that mmu_circ_0001442 is the primary circRNA responsive to DHT stimulation in mice with PND. The mmu_circ_0001442/miR-125a-3p/NUFIP2 axis was predicted and constructed according to the analysis of databases, including pita, miRanda, TargetScan, miRDB, micro-CDS, PolymiRTS, and TarBase v.8. Subsequently, the axis was verified by qPCR and double-luciferase reporter gene assays. In vitro, we found that DHT rarely had an effect on the growth of BV2 cells using the CCK-8 assay, but it attenuated the cytotoxic effect of lipopolysaccharide (LPS) on BV2 cells. In addition, we found that LPS stimulation promoted the release of proinflammatory cytokines, including IL-6 and TNF-α, in BV2 cells, whereas mmu_circ_0001442 knockdown and NUFIP2 knockdown partially abrogated this effect.
Taken together, DHT inhibited REDOX damage and neuroinflammation in the hippocampus to alleviate cognitive disorders in mice with PNDs via activation of the mmu_circ_0001442/miR-125a-3p/NUFIP2 axis. This study provides a novel rationale for developing DHT as a potential therapeutic agent for PND prevention.
围手术期神经认知障碍（PND）是老年患者术后恢复不佳的主要原因，且老年患者雄激素水平会随年龄增长而降低。然而，其潜在机制尚未完全阐明。
采用腹部手术构建PND小鼠模型。双氢睾酮（DHT）作为主要雄激素，可通过减少氧化还原损伤来改善患有PND的小鼠的认知功能。为阐明环状RNA（circRNA）在DHT改善PND小鼠认知功能中的作用，进行circRNA测序以分析小鼠海马体中circRNA的表达。
我们证实mmu_circ_0001442是PND小鼠中对DHT刺激产生反应的主要circRNA。根据对包括pita、miRanda、TargetScan、miRDB、micro-CDS、PolymiRTS和TarBase v.8在内的数据库分析，预测并构建了mmu_circ_0001442/miR-125a-3p/NUFIP2轴。随后，通过qPCR和双荧光素酶报告基因检测验证了该轴。在体外，我们使用CCK-8检测发现DHT对BV2细胞的生长几乎没有影响，但它减弱了脂多糖（LPS）对BV2细胞的细胞毒性作用。此外，我们发现LPS刺激促进了BV2细胞中促炎细胞因子（包括IL-6和TNF-α）的释放，而mmu_circ_0001442敲低和NUFIP2敲低部分消除了这种作用。
综上所述，DHT通过激活mmu_circ_0001442/miR-125a-3p/NUFIP2轴抑制海马体中的氧化还原损伤和神经炎症，以减轻PND小鼠的认知障碍。本研究为开发DHT作为预防PND的潜在治疗药物提供了新的理论依据。
