Isoflurane aggravates cognitive deficits in aged rats via lncRNA GABPB1-AS1/miR-361-3p-mediated NLRP3 inflammasome activation

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-09-17 DOI:10.1016/j.taap.2025.117571

Guorui Miao , Yiwei Zhang , Hui Wang

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引用次数: 0

Abstract

Objective

Postoperative cognitive dysfunction (POCD) following isoflurane (ISO) anesthesia in elderly patients is associated with neuroinflammation, but the molecular mechanisms remain unclear. This study aimed to elucidate the role and mechanism of long non-coding RNA (lncRNA) GA binding protein beta 1 subunit antisense RNA 1 (GABPB1-AS1) in ISO-induced POCD.

Methods

Aged rats were exposed to ISO to establish a POCD model. Cognitive deficits were assessed via morris water maze tests. Hippocampal expression of GABPB1-AS1, microglial activation markers (Iba1), pro−/anti-inflammatory cytokines, and NLRP3 inflammasome components was quantified using quantitative Reverse Transcription-PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and Western blotting. In vitro, BV-2 microglia treated with ISO were analyzed for polarization markers and cytokine secretion. Dual-luciferase assays validated interactions between GABPB1-AS1, microRNA-361-3p (miR-361-3p), and NLR family pyrin domain containing 3 (NLRP3).

Results

ISO upregulated hippocampal GABPB1-AS1 in aged rats, correlating with prolonged escape latency, reduced target quadrant time, and elevated pro-inflammatory cytokines. GABPB1-AS1 knockdown reversed these effects. In microglia, ISO increased GABPB1-AS1 expression, M1 polarization markers, and NLRP3 inflammasome activation, while suppressing M2 markers and miR-361-3p. GABPB1-AS1 acted as a competing endogenous RNA (ceRNA) to sponge miR-361-3p, relieving translational inhibition of NLRP3 and activating the NLRP3 inflammasome. GABPB1-AS1 knockdown restored miR-361-3p expression, suppressed NLRP3 inflammasome activation, and attenuated ISO-induced microglial M1 polarization and neuroinflammatory responses.

Conclusion

ISO induces POCD via the GABPB1-AS1/miR-361-3p/NLRP3 axis, driving microglial M1 polarization and neuroinflammation. Targeting this axis may offer therapeutic strategies to mitigate anesthesia-related cognitive decline in elderly patients.

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异氟醚通过lncRNA GABPB1-AS1/ mir -361-3p介导的NLRP3炎性体激活，加重老年大鼠的认知缺陷。

目的：异氟醚（ISO）麻醉后老年患者术后认知功能障碍（POCD）与神经炎症有关，但其分子机制尚不清楚。本研究旨在阐明长链非编码RNA (lncRNA) GA结合蛋白β 1亚基反义RNA 1 （GABPB1-AS1）在iso诱导的POCD中的作用及机制。方法：老龄大鼠暴露于ISO，建立POCD模型。认知缺陷通过morris水迷宫测试评估。采用定量逆转录- pcr （qRT-PCR）、酶联免疫吸附试验（ELISA）和Western blotting定量测定海马GABPB1-AS1、小胶质细胞激活标志物（Iba1）、促/抗炎细胞因子和NLRP3炎性小体成分的表达。体外用ISO处理BV-2小胶质细胞，分析其极化标记物和细胞因子分泌。双荧光素酶测定证实了GABPB1-AS1、microRNA-361-3p （miR-361-3p）和NLR家族pyrin domain containing 3 （NLRP3）之间的相互作用。结果：ISO上调老年大鼠海马GABPB1-AS1，与逃逸潜伏期延长、靶象限时间缩短、促炎细胞因子升高相关。GABPB1-AS1基因敲低逆转了这些作用。在小胶质细胞中，ISO增加了GABPB1-AS1表达、M1极化标记物和NLRP3炎性体激活，同时抑制了M2标记物和miR-361-3p。GABPB1-AS1作为竞争内源性RNA （ceRNA）海绵miR-361-3p，缓解NLRP3的翻译抑制并激活NLRP3炎性体。GABPB1-AS1敲低恢复了miR-361-3p的表达，抑制了NLRP3炎性体的激活，减弱了iso诱导的小胶质M1极化和神经炎症反应。结论：ISO通过GABPB1-AS1/miR-361-3p/NLRP3轴诱导POCD，驱动小胶质细胞M1极化和神经炎症。针对这一轴可能提供治疗策略，以减轻老年患者麻醉相关的认知能力下降。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.