Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou 311300, China.
Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou 311300, China.
Int Immunopharmacol. 2023 Apr;117:109880. doi: 10.1016/j.intimp.2023.109880. Epub 2023 Feb 27.
Ketamine is commonly used for sedation, analgesia and anesthetics. Much evidence has shown that it has an immune-regulatory effect. The cholinergic anti-inflammatory pathway mediated by α7nAChR is a prominent target of anti-inflammatory therapy. However, whether ketamine suppresses inflammatory levels in nerve cells by activating α7nAChR remains unknown. Lipopolysaccharide (LPS) was used to establish the neuroinflammation model in PC12 cells in vitro, and α7nAChR siRNA was transfected into PC12 cells 30 min before LPS to inhibit gene expression of α7nAChR. PC12 cells were stimulated with LPS for 24 h, and the indicators were detected at 2 h after GTS-21 and ketamine were added. The results showed that LPS increased the proportion of PC12 cells apoptosis, activated TLR4/MAPK/NF-κB signaling pathway, and increased the expression of interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Ketamine reduced the ratio of early apoptosis and late apoptosis of PC12, inhibited the entry of P65 into the nucleus, decreased the activation of TLR4/MAPK/NF-κB and improved neuroinflammation. However, the ameliorating effects of ketamine on neuronal apoptosis and neuroinflammation were inhibited in the α7nAChRi group. This indicated that α7nAChR played a key role in the anti-inflammatory process of ketamine. Low-dose ketamine inhibited TLR4/MAPK/NF-κB by activating the α7nAChR-mediated cholinergic anti-inflammatory pathway, thereby producing the protective effect on neuronal apoptosis and neuroinflammation.
氯胺酮通常用于镇静、镇痛和麻醉。大量证据表明，它具有免疫调节作用。α7nAChR 介导的胆碱能抗炎途径是抗炎治疗的一个突出靶点。然而，氯胺酮是否通过激活α7nAChR 抑制神经细胞中的炎症水平尚不清楚。脂多糖（LPS）用于体外 PC12 细胞建立神经炎症模型，LPS 刺激前 30min 将α7nAChR siRNA 转染至 PC12 细胞以抑制α7nAChR 基因表达。用 LPS 刺激 PC12 细胞 24h，加入 GTS-21 和氯胺酮 2h 后检测指标。结果表明，LPS 增加 PC12 细胞凋亡比例，激活 TLR4/MAPK/NF-κB 信号通路，增加白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的表达。氯胺酮降低 PC12 早期凋亡和晚期凋亡的比例，抑制 P65 进入细胞核，降低 TLR4/MAPK/NF-κB 的激活，改善神经炎症。然而，在α7nAChRi 组中，氯胺酮对神经元凋亡和神经炎症的改善作用受到抑制。这表明α7nAChR 在氯胺酮抗炎过程中起关键作用。低剂量氯胺酮通过激活α7nAChR 介导的胆碱能抗炎途径抑制 TLR4/MAPK/NF-κB，从而对神经元凋亡和神经炎症产生保护作用。
