Combination therapy with VELCADE and tissue plasminogen activator is neuroprotective in aged rats after stroke and targets microRNA-146a and the toll-like receptor signaling pathway.
Combination therapy with VELCADE and tissue plasminogen activator is neuroprotective in aged rats after stroke and targets microRNA-146a and the toll-like receptor signaling pathway.
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DOI：
10.1161/atvbaha.112.252619
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
Zhang ZG
中科院分区：
文献类型：
--
作者：
Zhang L;Chopp M;Liu X;Teng H;Tang T;Kassis H;Zhang ZG
Activation of the toll-like receptor (TLR) signaling pathway exacerbates ischemic brain damage. The present study tested the hypothesis that combination treatment with VELCADE and tissue plasminogen activator (tPA) modulates the TLR signaling pathway on cerebral vasculature, which leads to neuroprotection in aged rats after stroke. Focal cerebral ischemia acutely increased TLR2, TLR4, and interleukin-1 receptor activated kinases 1 (IRAK1) immunoreactivity on fibrin/fibrinogen positive vessels in aged rats. Monotherapy of tPA further amplified these signals. However, VELCADE in combination with tPA blocked stroke- and tPA-potentiated vascular TLR signals, leading to robust reduction of infarct volume compared with respective monotherapies. Quantitative RT-PCR analysis of cerebral endothelial cells isolated by laser capture microdissection revealed that the combination treatment increased miR-l46a levels, which was inversely associated with the reduction of vascular IRAK1 immunoreactivity. In vitro, fibrin upregulated IRAK1 and TLR4 expression and downregulated miR-146a on primary human cerebral endothelial cells. VELCADE elevated miR-146 levels and abolished fibrin-increased IRAK1 proteins. Stroke acutely activates the TLR signaling pathway on cerebral vasculature. Upregulation of miR-146a and inactivation of ischemia and tPA-potentiated TLR signaling pathway by VELCADE may play an important role in the neuroprotective effect of the combination therapy of VELCADE and tPA for acute stroke.
