紫草素通过抑制氧化应激和神经炎症在脑外伤后发挥神经保护作用
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E-mail:zzy@njmu.edu.cn;wxl145381@163.com

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R743.9

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国家自然科学基金(81771171);南京市卫生科技发展专项(YKK19076)


Shikonin exerts neuroprotective effects by anti⁃oxidative stress and inhibiting inflammation after brain trauma
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    摘要:

    目的:探究紫草素是否在创伤性脑损伤(traumatic brain injury,TBI)后发挥神经保护作用及其潜在机制。方法:将 40只小鼠随机分为假手术组(Sham组),脑外伤组(TBI组),脑外伤+1 mg/kg紫草素组(TBI+SK 1 mg/kg),脑外伤+5 mg/kg紫草素组 (TBI+SK 5 mg/kg)。构建创伤性颅脑损伤模型,并检测神经功能缺损评分(modified neurological severity score,mNSS),Beam⁃ walk平衡木实验检测小鼠运动功能;免疫荧光观察神经元的凋亡数量,伊文思蓝染色检测血脑屏障(blood brain barrier,BBB) 的完整性,Western blot和RT⁃PCR观察炎症水平(NLRP3/ASC/caspase1/IL⁃1β)的变化等。ELISA试剂盒检测损伤皮质周围水肿带氧化应激水平标志活性氧(reactive oxygen species,ROS)、脂质过氧化物(lipid peroxides,LPO)、丙二醛(malondialdehyde, MDA)以及抗氧化酶如超氧化物歧化酶(superoxide Dismutase,SOD)、谷胱甘肽过氧化物酶(glutathione peroxidase,GPx)活性的变化。体外培养神经元细胞系Neuro⁃2a(N2a)细胞和小胶质细胞系BV2细胞,并使用脂多糖(lipopolysaccharide,LPS)刺激模拟 TBI后颅内炎性环境。紫草素治疗后,通过Western blot检测BV2细胞炎症水平的变化,并通过流式细胞术检测LPS刺激后N2a 细胞凋亡的变化情况。结果:紫草素处理后可改善脑外伤后mNSS,发挥神经保护作用。紫草素可以抑制ROS、LPO、MDA的水平,促进SOD、GPx的升高,改善脑外伤后的氧化损伤。紫草素可以显著抑制脑外伤后的NF⁃κB/NLRP3的炎症激活,抑制损伤周围水肿带的小胶质细胞的激活。结论:紫草素可以抑制氧化应激,抑制NF⁃κB/NLRP3信号激活,减少凋亡,在脑外伤后发挥神经保护作用。

    Abstract:

    Objective:To explore the neuroprotective effects and the underlying mechanisms of shikonin(SK)after traumatic brain injury(TBI). Methods:Forty C57BL/6 mice were randomly assigned to 4 groups as follows:sham operation group(Sham group),TBI group,TBI + 1 mg/kg shikonin group(TBI+SK 1 mg/kg),TBI + 5 mg/kg shikonin group(TBI+SK 5 mg/kg). The modified neurological severity scores(mNSS)and the apoptosis of neurons after TBI(Neuron/TUNEL)was observed,the integrity of the blood brain barrier (BBB)was detected by Evans blue staining. Moreover,we used Western blot and RT⁃PCR to determine the expression of NLRP3/ASC/ IL⁃1β/Caspase1 and detected the changes in the levels of oxidative stress markers including ROS,LPO,MDA and antioxidant enzymes which includes SOD and GPx in the edema zone around the cortical injury. The Neuro⁃2a cell line and BV2 cell line were cultured in vitro,stimulated by LPS to establish the inflammatory environment. We used Western blot to observe the inflammatory response of BV2cells and observed that the changes of neuronal apoptosis by flow cytometry. Results:Shikonin treatment improved mNSS after TBI and exerted neuroprotective effects. Shikonin could inhibit the level of ROS,LPO,MDA,and promoted the increase of SOD,GPx, alleviating the oxidative damage after TBI. Moreover,shikonin significantly inhibited the inflammatory activation of NF ⁃ κB/NLRP3 after TBI,and inhibited the activation of microglia and astrocytes in the penumbra around the injury. Conclusion:Shikonin may play a neuroprotective effect after TBI via inhibiting the activation of NF⁃κB/NLRP3 and alleviating oxidative stress.

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朱海燕,赵晓晶,宋晶晶,张志远,王晓亮.紫草素通过抑制氧化应激和神经炎症在脑外伤后发挥神经保护作用[J].南京医科大学学报(自然科学版),2022,42(8):1055-1064

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  • 在线发布日期: 2022-08-07
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