氧化铈纳米颗粒减轻大鼠脓毒症相关的认知功能障碍

Investigation of Therapeutic Potential of Cerium Oxide Nanoparticles in Sepsis-Related Cognitive Impairments

目的探讨氧化铈纳米颗粒(CeO_(2) NPs)对脓毒症相关认知功能障碍的治疗潜力。方法采用X射线衍射仪和扫描电子显微镜对纳米颗粒进行表征。建立盲肠结扎穿孔(CLP)诱导的脓毒症大鼠模型。大鼠分别给予不同剂量的CeO_(2) NPs(4、8、16 mg/kg)进行灌胃处理,每日1次,连续7 d。采用神经行为学评价和Morris水迷宫实验评价大鼠的认知能力。给药7 d后采集海马组织和血样。采用ELISA法检测血清促炎细胞因子和氧化应激标志物水平。Western blot分析大鼠海马区基质金属蛋白酶(MMPs)的表达。结果CeO_(2) NPs为结晶态,直径约30 nm。与对照组的脓毒症大鼠相比,CeO_(2) NPs治疗的脓毒症大鼠的神经行为学评分和生存率显著提高,逃避潜伏期缩短,穿越平台的次数增加,游泳路径更长,在目标象限停留的时间更长。ELISA法结果显示CeO_(2) NPs能有效逆转CLP诱导的大鼠血清促炎细胞因子(IL-6、IL-1β、TNF-α)和氧化应激指标(SOD和CAT)水平的升高。此外,CeO_(2) NPs显著抑制了CLP诱导的脓毒症大鼠海马区中与血脑屏障破坏相关的MMPs-2和MMPs-9蛋白表达的上调。值得注意的是,CeO_(2) NPs的所有作用均具有剂量依赖性。结论CeO_(2) NPs可能通过减轻全身炎症反应、氧化应激和血脑屏障破坏来改善脓毒症大鼠的认知能力和生存率。

Objective To investigate the therapeutic potential of cerium oxide nanoparticles(CeO_(2) NPs)in sepsis-related cognitive impairments.Methods X-ray diffractometer and scanning electron microscopy were used to characterize the nanoparticles.Cecal ligation and puncture(CLP)-induced sepsis rat model was established.The rats were orally administered vehicle or different doses of CeO_(2) NPs(4,8,or 16 mg/kg)once daily for 7 days.Neurobehavioral assessment and Morris water maze test were carried out to evaluate the cognitive ability of the rats.The hippocampus and blood samples were collected at 7 days after treatment.ELISA was performed to measure the serum levels of proinflammatory cytokines and oxidative stress markers.Western blot analysis was conducted to determine the hippocampal expression of matrix metalloproteinases(MMPs).Results CeO_(2) NPs were crystalline with diameters of approximately 30 nm.Compared with vehicle-treated septic rats,CeO_(2) NPs-treated ones exhibited significantly increased neurobehavioral scores and survival rates,shortened escape latencies,increased numbers of platform crossings,as well as longer swimming paths and more time spent in the target quadrant.ELISA showed that CeO_(2) NPs effectively reversed CLP-induced elevations in the serum levels of proinflammatory cytokines(IL-6,IL-1β,and TNF-α)and oxidative stress indicators(SOD and CAT).Furthermore,CeO_(2) NPs strongly abolished CLP-induced upregulation of MMP-2 and MMP-9 protein expression related to blood-brain barrier disruption in the hippocampus of septic rats.Of note,all the effects of CeO_(2) NPs were dose dependent.Conclusion CeO_(2) NPs ameliorate cognitive ability and survival rate of septic rats possibly by alleviating systemic inflammation,oxidative stress,and blood-brain barrier disruption.