Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, USA; Department of Anaesthesia, Harvard Medical School, Boston, USA; Department of Immunology, Harvard Medical School, Boston, USA.
Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, USA; Department of Anaesthesia, Harvard Medical School, Boston, USA; Department of Immunology, Harvard Medical School, Boston, USA; Department of Anesthesiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Int Immunopharmacol. 2024 Nov 15;141:112975. doi: 10.1016/j.intimp.2024.112975. Epub 2024 Aug 19.
While a number of anesthetics has been shown potentially associated with neurotoxicity in the developing brain, dexmedetomidine, a drug that was rather recently introduced into the perioperative setting, is considered beneficial from neurological wellbeing. However, the underlying mechanism of how dexmedetomidine affects brain health remains to be determined. Based on our recent study, we hypothesized that dexmedetomidine would directly bind to and inhibit Toll-like receptor 4 (TLR4), a critical receptor largely expressed in microglia and responsible for neurological insult.
We used TLR4 reporter assays to test if dexmedetomidine attenuates TLR4 activation. Furthermore, a direct binding of dexmedetomidine on TLR4 was tested using photoactivatable medetomidine. Lastly, the effect of dexmedetomidine on ketamine (anesthetic)-induced neurotoxicity was tested in rat pups (P7).
We showed that dexmedetomidine attenuated TLR4 activation using reporter assay (IC = 5.8 µg/mL). Photoactivatable dexmedetomidine delineated its direct binding sites on TLR4. We also showed that dexmedetomidine attenuated microglia activation both in vitro and in vivo.
We proposed a novel mechanism of dexmedetomidine-mediated neuroprotection.
尽管已有多种麻醉剂被证明可能对发育中的大脑具有神经毒性，但右美托咪定是一种最近引入围手术期的药物，被认为对神经健康有益。然而，右美托咪定影响大脑健康的潜在机制仍有待确定。基于我们最近的研究，我们假设右美托咪定会直接结合并抑制 Toll 样受体 4（TLR4），TLR4 是一种在小胶质细胞中大量表达的关键受体，负责神经损伤。
我们使用 TLR4 报告基因检测来测试右美托咪定是否能减弱 TLR4 的激活。此外，我们使用光活化的右美托咪定测试了右美托咪定与 TLR4 的直接结合。最后，我们在 P7 幼鼠中测试了右美托咪定对氯胺酮（麻醉剂）诱导的神经毒性的影响。
我们通过报告基因检测表明右美托咪定可减弱 TLR4 的激活（IC=5.8μg/mL）。光活化的右美托咪定描绘了其与 TLR4 的直接结合部位。我们还表明，右美托咪定在体外和体内均减弱了小胶质细胞的激活。
我们提出了右美托咪定介导的神经保护的新机制。
