Lysosomal rupture, necroapoptotic interactions and potential crosstalk between cysteine proteases in neurons shortly after focal ischemia
Lysosomal rupture, necroapoptotic interactions and potential crosstalk between cysteine proteases in neurons shortly after focal ischemia
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DOI：
10.1016/j.nbd.2010.06.003
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发表时间：
2010-10-01
影响因子：
6.1
通讯作者：
Dalkara, Turgay
中科院分区：
文献类型：
--
作者：
Kilinc, Muenire;Gursoy-Ozdemir, Yasemin;Dalkara, Turgay
缺血性细胞死亡是一个复杂的过程，细胞凋亡和坏死之间的最初区别似乎过于简单化。我们以前报道过，在质膜破裂的缺血性神经元中，凋亡机制也是活跃的。在本研究中，我们研究了另一种坏死特征，溶酶体破裂，与小鼠脑中的凋亡机制的细胞共定位，并评估了半胱氨酸蛋白酶之间的潜在相互作用。在缺血/再灌注后1-4小时，溶酶体酶溢出到细胞质中，表明溶酶体膜完整性迅速丧失，如坏死中所发生的那样。同样的神经元也表现出caspase-3和Bid切割，和细胞色素C的释放。在大多数神经元中，Caspase-3活性先于组织蛋白酶-B渗漏，并在12小时后下降，而溶酶体渗漏继续增加。组织蛋白酶-B和半胱天冬酶-3的同时抑制提供了比单独使用每种抑制剂获得的显著更好的神经保护。这些数据表明，坏死和凋亡机制可能在缺血发作时开始在同一细胞内同时或独立地起作用，以确保受损神经元的死亡。因此，联合抑制半胱氨酸蛋白酶可能会消除替代死亡途径之间的潜在转变，并提高中风治疗的成功率。(c)2010年爱思唯尔公司All rights reserved.
Ischemic cell death is a complex process and the initial distinction between apoptosis and necrosis appears to be an oversimplification. We previously reported that in ischemic neurons with disrupted plasmalemma, apoptotic mechanisms were also active. In the present study, we investigated cellular co-localization of another necrotic feature, lysosomal rupture, with apoptotic mechanisms in the mouse brain and assessed the potential interactions between cysteine proteases. The lysosomal enzymes were spilled into the cytoplasm 1-4 h after ischemia/reperfusion, suggesting that lysosomal membrane integrity was rapidly lost, as occurs in necrosis. The same neurons also exhibited caspase-3 and Bid cleavage, and cytochrome-c release. Caspase-3 activity preceded cathepsin-B leakage in most neurons, and declined by 12 h, while lysosomal leakage continued to increase. Concurrent inhibition of cathepsin-B and caspase-3 provided significantly better neuroprotection than obtained with separate use of each inhibitor. These data suggest that necrotic and apoptotic mechanisms may act both in concert as well as independently within the same cell beginning at the onset of ischemia to ensure the demise of damaged neurons. Therefore, combined inhibition of cysteine proteases may abrogate potential shifts between alternative death pathways and improve the success of stroke treatments. (c) 2010 Elsevier Inc. All rights reserved.