SS-31对蛛网膜下腔出血大鼠模型早期脑损伤及NLRP3炎性小体的影响
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摘要
目的探讨线粒体靶向抗氧化肽SS-31对Nod样受体蛋白3(NLRP3)炎性小体的影响以及对蛛网膜下腔出血(SAH)早期脑损伤的作用。方法将120只成年雄性大鼠随机分为4组:假手术组(Sham组)、SAH组、SAH+载体组(SAH+V组)和SAH+SS-31组,对每组大鼠进行神经功能评估,脑含水量和活性氧(ROS)测量,蛋白质免疫印迹分析NLRP3、凋亡相关斑点样蛋白(ASC)和caspase-1的蛋白表达情况,采用退化神经元染色(Fluoro-Jade C)、末端脱氧核苷酸转移酶介导的dUTP缺口末端标记(TUNEL)和DNA聚合酶I介导的生物素标记的(dATP)缺口平移(PANT)染色分析神经细胞死亡情况。结果 SS-31治疗可以增加大鼠神经功能评分,使SAH损伤后的脑水肿减少,ROS的含量显著降低,抑制SAH后大鼠NLRP3炎性小体,显著降低IL-1β和IL-18的表达,显著减少Fluoro-Jade C阳性细胞、PANT阳性细胞和TUNEL阳性细胞的数量。结论线粒体靶向抗氧化肽SS-31可抑制NLRP3炎性小体,并对蛛网膜下腔出血早期脑损伤具有保护作用。
Objective To investigate the effect of mitochondria-targeted antioxidant peptide SS-31 on NLRP3 inflammatory corpuscles and early brain injury in subarachnoid hemorrhage(SAH). Methods 120 adult male rats were randomly divided into 4 groups, including sham operation group(Sham group), SAH group, SAH+carrier group(SAH+V group) and SAH+SS-31 group. Neurological function was assessed, brain water content and reactive oxygen species(ROS) were measured, immunoblotting analysis of NLRP3, ASC and caspase-1 protein expression was performed. Fluoro-Jade C, TUNEL and PANT staining were used to analyze neuronal cell death. Results SS-31 treatment was shown to be able to increase the neurological function score of rats, reducing brain edema after SAH injury, significantly reducing ROS content, inhibit NLRP3 inflammatory body in rats after SAH, and significantly reducing the expression of IL-1β and IL-18. Meanwhile, the number of Fluoro-Jade C positive cells, PANT positive cells and TUNEL positive cells were observed to be significantly reduced. Conclusion Mitochondria-targeted antioxidant peptide SS-31 can inhibit NLRP3 inflammatory corpuscles and protect against early brain injury in subarachnoid hemorrhage.
Objective To investigate the effect of mitochondria-targeted antioxidant peptide SS-31 on NLRP3 inflammatory corpuscles and early brain injury in subarachnoid hemorrhage(SAH). Methods 120 adult male rats were randomly divided into 4 groups, including sham operation group(Sham group), SAH group, SAH+carrier group(SAH+V group) and SAH+SS-31 group. Neurological function was assessed, brain water content and reactive oxygen species(ROS) were measured, immunoblotting analysis of NLRP3, ASC and caspase-1 protein expression was performed. Fluoro-Jade C, TUNEL and PANT staining were used to analyze neuronal cell death. Results SS-31 treatment was shown to be able to increase the neurological function score of rats, reducing brain edema after SAH injury, significantly reducing ROS content, inhibit NLRP3 inflammatory body in rats after SAH, and significantly reducing the expression of IL-1β and IL-18. Meanwhile, the number of Fluoro-Jade C positive cells, PANT positive cells and TUNEL positive cells were observed to be significantly reduced. Conclusion Mitochondria-targeted antioxidant peptide SS-31 can inhibit NLRP3 inflammatory corpuscles and protect against early brain injury in subarachnoid hemorrhage.
引文
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[12] RAMACHANDRAN S,LOGANATHANN S,CHEERAN V,et al.Forskolin attenuates doxorubicin-induced accumulation of asymmetric dimethylarginine and sadenosylhomocysteine via methyltransferase activity in leukemic monocytes[J].Leuk Res Rep,2018,9(4):28-35.
[13] SHI L,LIANG F,ZHENG J,et al.Melatonin regulates apoptosis and autophagy via ROS-MST1 pathway in subarachnoid hemorrhage[J].Front Mol Neurosci,2018,11(2):93-97.
[14] LETTERIA M,DOMENICO P,MARIAGRAZIA R,et al.ROS-mediated NLRP3 inflammasome activation in brain,heart,kidney,and testis ischemia/reperfusion injury[J].Oxid Med Cell Longev,2016,20(6):1-10.
[2] 邓晓红,张京芬.动脉瘤性蛛网膜下腔出血后早期脑损伤病理生理的研究进展[J].世界最新医学信息文摘,2018,18(5):33-35.
[3] 杨柳,张敏,贺曦,等.不同类型急性神经损伤患者并发低钠血症的临床特征及预后分析[J].中国急救医学,2018,20(2):159-163.
[4] CHRIST A,GUNTHER P,LAUTERBACH M,et al.Western diet triggers NLRP3-dependent innate immune reprogramming[J].Cell,2018,172(1):162-175.
[5] HOU Y,WANG Y,HE Q,et al.Nrf2 inhibits NLRP3 inflammasome activation through regulating Trx1/TXNIP complex in cerebral ischemia reperfusion injury[J].Behav Brain Res,2018,33(6):32-39.
[6] 周建,李争争,陈政纲,等.线粒体靶向抗氧化剂SS31对大鼠蛛网膜下腔出血后早期脑损伤的保护作用[J].中南大学学报(医学版),2017,42(9):1003-1009.
[7] FRITZ D,MUSIAL M K.Neurological assessment[J].Home Healthc Now,2016,34(1):16-22.
[8] 嵇朋,周衡.早期肠内营养支持对高分级动脉瘤性蛛网膜下腔出血患者营养指标、炎性因子及预后的影响[J].中国卒中杂志,2018,13(7):671-675.
[9] 李玉雄,郭子运,张雄新.脑卒中后抑郁患者的炎性因子和脑源性神经营养因子水平变化及相关性分析[J].解放军医药杂志,2018,30(12):101-104.
[10] 吴晓升,项静,刘靖华.线粒体在NLRP3炎性小体激活过程中的双向调节作用[J].现代免疫学,2018,38(4):333-336.
[11] 聂晟.氟西汀介导的自噬通过抑制NLRP3炎症小体的活化改善大鼠蛛网膜下腔出血后早期脑损伤[D].杭州:浙江大学,2017.
[12] RAMACHANDRAN S,LOGANATHANN S,CHEERAN V,et al.Forskolin attenuates doxorubicin-induced accumulation of asymmetric dimethylarginine and sadenosylhomocysteine via methyltransferase activity in leukemic monocytes[J].Leuk Res Rep,2018,9(4):28-35.
[13] SHI L,LIANG F,ZHENG J,et al.Melatonin regulates apoptosis and autophagy via ROS-MST1 pathway in subarachnoid hemorrhage[J].Front Mol Neurosci,2018,11(2):93-97.
[14] LETTERIA M,DOMENICO P,MARIAGRAZIA R,et al.ROS-mediated NLRP3 inflammasome activation in brain,heart,kidney,and testis ischemia/reperfusion injury[J].Oxid Med Cell Longev,2016,20(6):1-10.