Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke.
Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke.
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DOI：
10.1038/s41598-018-24350-x
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发表时间：
2018-04-13
影响因子：
4.6
通讯作者：
Ishrat T
中科院分区：
文献类型：
--
作者：
Ismael S;Zhao L;Nasoohi S;Ishrat T
NOD样受体蛋白(NLRP3)-炎症小体的激活被认为在脑缺血/再灌注损伤过程中介导了对脑损伤的炎症反应。因此，我们推测选择性NLRP3-炎症体抑制剂MCC950对小鼠大脑中动脉短暂性闭塞(TMCAO)模型具有保护作用。大鼠大脑中动脉闭塞60 后，分别于1 h和3 h腹腔注射MCC95 0(5 0 mg/kg)或生理盐水。I/R 24 h后，检测小鼠的神经功能状况，分析脑梗塞面积，并测定NLRP3炎症体和细胞凋亡标志物。采用分光光度法测定血红蛋白(Hb)含量作为脑出血的标志物。与生理盐水对照组相比，MCC950组小鼠的脑梗塞、水肿和Hb含量显著减少，同时神经功能障碍得到改善。MCC950降低半影区NLRP3-炎症体裂解产物Caspase-1和IL-1β(IL-1β)的表达。MCC95 0的这些保护作用与降低肿瘤坏死因子α水平、多聚腺苷二磷酸核糖聚合酶(PARP)和caspase3的裂解以及与磷酸化程度较低的NFκBp6 5和IκBα水平平行。综上所述，这些数据表明，MCC950抑制NLRP3-炎症小体在缺血性卒中模型中具有治疗潜力。需要对治疗效果和方案进行进一步的研究，以确认MCC950治疗是否可能成为临床试验的有前途的候选药物。
Activation of the NOD-like receptor protein (NLRP3)-inflammasome has been postulated to mediate inflammatory responses to brain damage during ischemic/reperfusion (I/R) injury. We therefore hypothesized that MCC950, a selective NLRP3-inflammasome inhibitor provides protection in mouse model of transient middle cerebral artery occlusion (tMCAO). Focal cerebral ischemia was induced by 60 min tMCAO followed by intraperitoneal administration of MCC950 (50 mg/kg) or saline at 1 h and 3 h post-occlusion. After 24 h of I/R, mice were tested for neurological outcome and were sacrificed for the analysis of infarct size and estimating NLRP3-inflammasome and apoptotic markers as well. Spectrophotometric method was used to determine hemoglobin (Hb) content as a marker of intracerebral hemorrhage. MCC950-treated mice showed a substantial reduction in infarction, edema and Hb content compared to saline controls in parallel with improved neurological deficits. MCC950 reduced expression of NLRP3-inflammasome cleavage products Caspase-1 and interlukin-1β (IL-1β) in penumbral region. These protective effects of MCC950 were associated with decreased TNF-α levels as well as poly (ADP-ribose) polymerase (PARP) and Caspase-3 cleavage and paralleled less phosphrylated NFκBp65 and IκBα levels. Taken together, these data indicate that inhibition of NLRP3-inflammasome with MCC950 has therapeutic potential in ischemic stroke models. Further investigations into the therapeutic efficacy and protocols are needed to confirm whether MCC950 treatment could be a promising candidate for clinical trials.
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影响因子：
37.8
作者：
Go AS;Mozaffarian D;Roger VL;Benjamin EJ;Berry JD;Blaha MJ;Dai S;Ford ES;Fox CS;Franco S;Fullerton HJ;Gillespie C;Hailpern SM;Heit JA;Howard VJ;Huffman MD;Judd SE;Kissela BM;Kittner SJ;Lackland DT;Lichtman JH;Lisabeth LD;Mackey RH;Magid DJ;Marcus GM;Marelli A;Matchar DB;McGuire DK;Mohler ER 3rd;Moy CS;Mussolino ME;Neumar RW;Nichol G;Pandey DK;Paynter NP;Reeves MJ;Sorlie PD;Stein J;Towfighi A;Turan TN;Virani SS;Wong ND;Woo D;Turner MB;American Heart Association Statistics Committee and Stroke Statistics Subcommittee
通讯作者：
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
DOI：
10.1016/j.bbi.2017.02.014
发表时间：
2017-05
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Abdul-Muneer PM;Alikunju S;Mishra V;Schuetz H;Szlachetka AM;Burnham EL;Haorah J
通讯作者：
Haorah J
影响因子：
8.3
作者：
Jovin TG;Albers GW;Liebeskind DS;STAIR IX Consortium
通讯作者：
STAIR IX Consortium
影响因子：
6.3
作者：
Abulafia, Denise P.;Vaccari, Juan Pablo de Rivero;Dietrich, W. Dalton
通讯作者：
Dietrich, W. Dalton
影响因子：
168.9
作者：
Kalra, Lalit;Irshad, Saddif;Rebollo-Mesa, Irene
通讯作者：
Rebollo-Mesa, Irene