Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630 Guangdong, China.
Department of Anesthesiology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, 637000 Sichuan, China.
Neural Plast. 2022 Apr 19;2022:1353778. doi: 10.1155/2022/1353778. eCollection 2022.
Surgery-induced microglial activation is critical in mediating postoperative cognitive dysfunction (POCD) in elderly patients, where the important protective effect of dexmedetomidine has been indicated. However, the mechanisms of action of dexmedetomidine during the neuroinflammatory response that underlies POCD remain largely unknown. We found that lipopolysaccharide (LPS) induced substantial inflammatory responses in primary and BV2 microglial cells. The screening of differentially expressed miRNAs revealed that miR-103a-3p was downregulated in these cell culture models. Overexpression of miR-103a-3p mimics and inhibitors suppressed and enhanced the release of inflammatory factors, respectively. VAMP1 expression was upregulated in LPS-treated primary and BV-2 microglial cells, and it was validated as a downstream target of miR-103-3p. VAMP1-knockdown significantly inhibited the LPS-induced inflammatory response. Dexmedetomidine treatment markedly inhibited LPS-induced inflammation and the expression of VAMP1, and miR-103a-3p expression reversed this inhibition. Moreover, dexmedetomidine mitigated microglial activation and the associated inflammatory response in a rat model of surgical trauma that mimicked POCD. In this model, dexmedetomidine reversed miR-103a-3p and VAMP1 expression; this effect was abolished by miR-103a-3p overexpression. Taken together, the data show that miR-103a-3p/VAMP1 is critical for surgery-induced microglial activation of POCD.
手术引起的小胶质细胞激活在介导老年患者术后认知功能障碍（POCD）中起关键作用，其中右美托咪定的重要保护作用已得到证实。然而，在POCD 所基于的神经炎症反应中，右美托咪定的作用机制在很大程度上尚不清楚。我们发现脂多糖（LPS）诱导原代和 BV2 小胶质细胞产生大量炎症反应。差异表达 miRNA 的筛选表明，miR-103a-3p 在这些细胞培养模型中下调。miR-103a-3p 模拟物和抑制剂的过表达分别抑制和增强炎症因子的释放。VAMP1 表达在 LPS 处理的原代和 BV-2 小胶质细胞中上调，并被验证为 miR-103-3p 的下游靶标。VAMP1 敲低显著抑制 LPS 诱导的炎症反应。右美托咪定处理显著抑制 LPS 诱导的炎症和 VAMP1 的表达，miR-103a-3p 的表达逆转了这种抑制。此外，右美托咪定减轻了手术创伤大鼠模型中小胶质细胞的激活和相关炎症反应，该模型模拟了 POCD。在该模型中，右美托咪定逆转了 miR-103a-3p 和 VAMP1 的表达；这种作用被 miR-103a-3p 的过表达所消除。总之，数据表明 miR-103a-3p/VAMP1 对手术诱导的 POCD 中小胶质细胞的激活至关重要。
