DHT inhibits REDOX damage and neuroinflammation to reduce PND occurrence in aged mice via mmu_circ_0001442/miR-125a-3p/NUFIP2 axis.

Abstract

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.