Tissue Plasminogen Activator Neurotoxicity is Neutralized by Recombinant ADAMTS 13.
Tissue Plasminogen Activator Neurotoxicity is Neutralized by Recombinant ADAMTS 13.
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重组 ADAMTS 13 中和组织纤溶酶原激活剂神经毒性
DOI：
10.1038/srep25971
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发表时间：
2016-05-16
影响因子：
4.6
通讯作者：
Zhao BQ
中科院分区：
文献类型：
--
作者：
Fan M;Xu H;Wang L;Luo H;Zhu X;Cai P;Wei L;Lu L;Cao Y;Ye R;Fan W;Zhao BQ
组织型纤溶酶原激活剂（tPA）是治疗缺血性脑卒中的有效药物，但其神经毒性是一个值得关注的问题。在这里，我们测试的假设，重组ADAMTS 13（rADAMTS 13）将减少tPA神经毒性的小鼠模型中风。我们发现，与中风后48小时仅用tPA治疗的小鼠相比，用rADAMTS 13与tPA组合治疗显著减少了梗死体积。与单独用tPA或媒介物处理的小鼠相比，组合处理显著改善神经缺陷。这些神经保护作用与缺血血管中纤维蛋白沉积的显著减少和缺血脑中较轻的细胞死亡有关。rADAMTS 13对tPA神经毒性的作用被N-甲基-D-天冬氨酸（NMDA）受体拮抗剂M-801模拟，并被注射NMDA消除。此外，rADAMTS 13通过阻断tPA与NMDA受体NR 2B的相互作用以及随之而来的NR 2B磷酸化和ERK 1/2激活来预防tPA的神经毒性作用。最后，NR 2B特异性NMDA受体拮抗剂艾芬地尔消除tPA神经毒性，rADAMTS 13治疗没有进一步的有益作用。我们的数据表明，rADAMTS 13和tPA的组合可能会提供一种新的治疗缺血性中风，减少外源性tPA的神经毒性作用。
Tissue plasminogen activator (tPA) is an effective treatment for ischemic stroke, but its neurotoxicity is a significant problem. Here we tested the hypothesis that recombinant ADAMTS 13 (rADAMTS 13) would reduce tPA neurotoxicity in a mouse model of stroke. We show that treatment with rADAMTS 13 in combination with tPA significantly reduced infarct volume compared with mice treated with tPA alone 48 hours after stroke. The combination treatment significantly improved neurological deficits compared with mice treated with tPA or vehicle alone. These neuroprotective effects were associated with significant reductions in fibrin deposits in ischemic vessels and less severe cell death in ischemic brain. The effect of rADAMTS13 on tPA neurotoxicity was mimicked by the N-methyl-D-aspartate (NMDA) receptor antagonist M-801 and was abolished by injection of NMDA. Moreover, rADAMTS 13 prevents the neurotoxicity effect of tPA, by blocking its interaction with the NMDA receptor NR2B and the attendant phosphorylation of NR2B and activation of ERK1/2. Finally, the NR2B-specific NMDA receptor antagonist ifenprodil abolished tPA neurotoxicity and rADAMTS 13 treatment had no further beneficial effect. Our data suggest that the combination of rADAMTS 13 and tPA may provide a novel treatment of ischemic stroke by diminishing the neurotoxic effects of exogenous tPA.