Department of Anesthesiology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, No.44 Xiaoheyan road, Dadong district, Shenyang, 110042, Liaoning, China.
BMC Anesthesiol. 2022 Apr 29;22(1):126. doi: 10.1186/s12871-022-01661-1.
Dexmedetomidine (DEX) is a selective agonist of α2-adrenergic receptors with anesthetic activity and neuroprotective benefits. However, its mechanism of action at the molecular level remains poorly defined. In this study, we investigated the protective effects of DEX on oxygen-glucose deprivation/ reperfusion (OGD/R)-induced neuronal apoptosis in PC12 cells, and evaluated its underlying mechanism(s) of neuroprotection and anti-inflammation.
An OGD/R model in PC12 cells was established. PC12 cells were cultured and divided into control, OGD/R, and OGD/R + DEX (1 μM, 10 μM, 50 μM) groups. Cell apoptosis was analyzed by flow cytometry and expression profiles were determined by qRT-PCR, western blot analysis, and enzyme linked immunosorbent assays (ELISA). The interaction between miRNA and its downstream targets was evaluated through luciferase reporter assays.
DEX significantly decreased apoptosis rates and inhibited interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) release (P < 0.05). While expression of the pro-apoptotic proteins Bax and Caspase-3 was down-regulated, expression of Bcl-2 was upregulated in a dose-dependent manner (P < 0.05). Interestingly, miR-17-5p expression was down-regulated in the OGD/R group (compared to controls). Toll-like receptor 4 (TLR4), a key regulator of nuclear factor kappa-B (NF-κB) signaling, was identified as a novel target of miR-17-5p in PC12 cells. miR-17-5p expression was upregulated in the OGD/R + DEX group, suppressing TLR4 expression and reducing the secretion of proinflammatory cytokines.
DEX inhibits OGD/R-induced inflammation and apoptosis in PC12 cells by increasing miR-17-5p expression, downregulating TLR4, and inhibiting NF-κB signaling.
右美托咪定（DEX）是一种选择性α2-肾上腺素能受体激动剂，具有麻醉活性和神经保护作用。然而，其在分子水平上的作用机制仍不清楚。在这项研究中，我们研究了 DEX 对 PC12 细胞氧葡萄糖剥夺/再灌注（OGD/R）诱导的神经元凋亡的保护作用，并评估了其神经保护和抗炎的潜在机制。
建立 PC12 细胞 OGD/R 模型。培养 PC12 细胞并分为对照组、OGD/R 组和 OGD/R+DEX（1μM、10μM、50μM）组。通过流式细胞术分析细胞凋亡，通过 qRT-PCR、western blot 分析和酶联免疫吸附试验（ELISA）测定表达谱。通过荧光素酶报告实验评估 miRNA 与其下游靶标的相互作用。
DEX 可显著降低细胞凋亡率，并抑制白细胞介素 1β（IL-1β）、肿瘤坏死因子-α（TNF-α）和白细胞介素 6（IL-6）的释放（P<0.05）。促凋亡蛋白 Bax 和 Caspase-3 的表达下调，Bcl-2 的表达呈剂量依赖性上调（P<0.05）。有趣的是，OGD/R 组中 miR-17-5p 的表达下调（与对照组相比）。Toll 样受体 4（TLR4）是核因子 kappa-B（NF-κB）信号通路的关键调节因子，被鉴定为 PC12 细胞中 miR-17-5p 的新靶标。DEX 上调 miR-17-5p 的表达，抑制 TLR4 的表达，减少促炎细胞因子的分泌，从而抑制 OGD/R 诱导的炎症和细胞凋亡。
DEX 通过增加 miR-17-5p 的表达、下调 TLR4 以及抑制 NF-κB 信号通路，抑制 OGD/R 诱导的 PC12 细胞炎症和凋亡。
