Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital, Beijing, China.
Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
Cell Death Dis. 2019 Feb 18;10(3):167. doi: 10.1038/s41419-019-1416-5.
Sepsis is life-threatening and often leads to acute brain damage. Dexmedetomidine, an α-adrenoceptor agonist, has been reported to possess neuroprotective effects against various brain injury but underlying mechanisms remain elusive. In this study, in vitro and in vivo models of sepsis were used to explore the effects of dexmedetomidine on the inflammasome activity and its associated glia pyroptosis and neuronal death. In vitro, inflammasome activation and pyroptosis were found in astrocytes following lipopolysaccharide (LPS) exposure. Dexmedetomidine significantly alleviated astrocyte pyroptosis and inhibited histone release induced by LPS. In vivo, LPS treatment in rats promoted caspase-1 immunoreactivity in astrocytes and caused an increase in the release of pro-inflammatory cytokines of IL-1β and IL-18, resulting in neuronal injury, which was attenuated by dexmedetomidine; this neuroprotective effect was abolished by α-adrenoceptor antagonist atipamezole. Dexmedetomidine significantly reduced the high mortality rate caused by LPS challenge. Our data demonstrated that dexmedetomidine may protect glia cells via reducing pyroptosis and subsequently protect neurons, all of which may preserve brain function and ultimately improve the outcome in sepsis.
脓毒症具有生命威胁性，常导致急性脑损伤。去甲肾上腺素能α2 受体激动剂右美托咪定已被报道具有针对各种脑损伤的神经保护作用，但潜在机制仍不清楚。在这项研究中，使用了脓毒症的体外和体内模型，以探讨右美托咪定对小胶质细胞细胞焦亡及其相关炎症小体活性的影响以及神经元死亡的影响。在体外，脂多糖（LPS）暴露后发现星形胶质细胞中存在炎症小体激活和细胞焦亡。右美托咪定可显著减轻星形胶质细胞的细胞焦亡，并抑制 LPS 诱导的组蛋白释放。在体内，LPS 处理可促进大鼠星形胶质细胞中半胱氨酸天冬氨酸蛋白酶-1（caspase-1）免疫反应，并导致促炎细胞因子白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）的释放增加，从而导致神经元损伤，而右美托咪定可减轻这种损伤；这种神经保护作用被α2 受体拮抗剂阿替美唑所阻断。右美托咪定可显著降低 LPS 攻击引起的高死亡率。我们的数据表明，右美托咪定可能通过减少细胞焦亡来保护神经胶质细胞，进而保护神经元，所有这些都可能维持脑功能并最终改善脓毒症的预后。
