Liao Zhimin, Ou Xiaofeng, Zhou Cheng, Ma Daqing, Zhao Hailin, Huang Han
Department of Anesthesiology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu, China.
Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China.
Front Pharmacol. 2022 Dec 2;13:1002920. doi: 10.3389/fphar.2022.1002920. eCollection 2022.
Neonatal sepsis is known to cause neurodevelopment impairment and has been reported to increase risks for neurological/psychiatric disorders. In this study, we investigated the effect of xenon, a well-known potent neuroprotective gas, on neonatal sepsis-induced neurodevelopment impairment in rats together with underlying mechanism by focusing on receptor-interacting protein kinase (RIP) mediated neuronal necroptosis. 3-day-old Sprague-Dawley rat pups were exposed to either 70% xenon or N balanced with O for 6 h, during which lipopolysaccharide (LPS) was injected intraperitoneally for 3 times (500 μg/kg for the 1st and 250 μg/kg for the second and third dose; = 6-10/group). In another cohort of 3-day-old rat pups, intracerebroventricular injection of necrostatin-1 (4 µg in 4 µl saline, a RIP-1-targeted inhibitor of necroptosis) was performed 20 min after the third dose of LPS. The learning ability and memory were assessed 25 days after LPS injection. Then, their hippocampus was collected for neuronal necroptosis with RIP and MIKL assessments using western blot and immunostaining. Systemic and neuro-inflammation was also assessed. LPS insult resulted in elevation of pro-inflammatory cytokine TNF-𝝰 and IL-6, caused neuronal necroptosis and damaged synaptic integrity at the brain developing stage, which finally led to the long-term cognitive impairment. Xenon inhibited necroptosis associated mediator RIP-1, RIP-3, and MLKL activation, protected neurons and attenuated cognitive dysfunction induced by LPS. Like xenon, the similar pattern changes induced by a RIP-1 inhibitor Necrostatin-1 were also found. This study indicates that necroptosis is involved in neonatal sepsis-induced neurofunctional impairments and xenon may be a novel therapeutic strategy to prevent/treat cognitive impairment in neonatal septic patients.
已知新生儿败血症会导致神经发育障碍，并且据报道会增加患神经/精神疾病的风险。在本研究中，我们研究了一种著名的强效神经保护气体氙对大鼠新生儿败血症诱导的神经发育障碍的影响以及潜在机制，重点关注受体相互作用蛋白激酶（RIP）介导的神经元坏死性凋亡。将3日龄的Sprague-Dawley大鼠幼崽暴露于70%氙气或与氧气平衡的氮气中6小时，在此期间腹腔注射脂多糖（LPS）3次（第1次剂量为500μg/kg，第2次和第3次剂量为250μg/kg；每组n = 6 - 10）。在另一组3日龄大鼠幼崽中，在第三次注射LPS后20分钟进行脑室内注射坏死抑制剂-1（4μg溶于4μl生理盐水中，一种靶向RIP-1的坏死性凋亡抑制剂）。在注射LPS后25天评估学习能力和记忆力。然后，收集它们的海马体，通过蛋白质印迹法和免疫染色评估RIP和MIKL以检测神经元坏死性凋亡。还评估了全身炎症和神经炎症。LPS损伤导致促炎细胞因子TNF-α和IL-6升高，在大脑发育阶段引起神经元坏死性凋亡并破坏突触完整性，最终导致长期认知障碍。氙抑制坏死性凋亡相关介质RIP-1、RIP-3和MLKL的激活，保护神经元并减轻LPS诱导的认知功能障碍。与氙类似，还发现了RIP-1抑制剂坏死抑制剂-1诱导的类似模式变化。本研究表明，坏死性凋亡参与新生儿败血症诱导的神经功能障碍，氙可能是预防/治疗新生儿败血症患者认知障碍的一种新的治疗策略。
