Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury.
Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury.
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DOI：
10.4103/1673-5374.226394
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发表时间：
2018-03
影响因子：
6.1
通讯作者：
Chen HH
中科院分区：
文献类型：
--
作者：
Cruz SA;Qin Z;Stewart AFR;Chen HH
缺血性脑损伤通过半胱天冬酶激活引起的细胞凋亡和通过与肿瘤坏死因子-α (TNF-α)/死亡受体相关的受体相互作用蛋白激酶（RIPK）的激活引起的坏死凋亡触发神经元细胞死亡。最近的证据表明，在许多动物模型中，RIPK抑制剂具有神经保护作用并减轻缺血性脑损伤，然而，大多数尚未进行临床试验，在人类中的安全性仍然存在问题。Dabrafenib最初被确定为B-raf抑制剂，目前用于治疗黑色素瘤，后来发现在微摩尔浓度下是一种有效的RIPK3抑制剂。在这里，我们研究了Dabrafenib是否会对光血栓形成的缺血性脑损伤小鼠显示类似的神经保护作用。在光血栓性局灶性缺血性损伤1小时后，以10 mg/kg的剂量腹腔注射Dabrafenib，第二天C57BL6小鼠梗死灶大小明显减少，TNF-α上调明显减弱。然而，随后的低剂量（5mg /kg/天）在4天后未能维持这种神经保护作用。Dabrafenib阻断脂多糖诱导的骨髓源性巨噬细胞TNF-α的活化，提示Dabrafenib可能减弱缺血性脑损伤后TNF-α诱导的坏死坏死途径。由于Dabrafenib已经在临床用于治疗黑色素瘤，它可能会被重新用于中风治疗。
Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases (RIPK) associated with the tumor necrosis factor-alpha (TNF-α)/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and alleviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar concentrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-α. However, subsequent lower doses (5 mg/kg/day) failed to sustain this neuroprotective effect after 4 days. Dabrafenib blocked lipopolysaccharides-induced activation of TNF-α in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-α-induced necroptotic pathway after ischemic brain injury. Since Dabrafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.
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影响因子：
3.7
作者：
King AJ;Arnone MR;Bleam MR;Moss KG;Yang J;Fedorowicz KE;Smitheman KN;Erhardt JA;Hughes-Earle A;Kane-Carson LS;Sinnamon RH;Qi H;Rheault TR;Uehling DE;Laquerre SG
通讯作者：
Laquerre SG
影响因子：
4.8
作者：
Khwaja, A;Tatton, L
通讯作者：
Tatton, L
DOI：
10.1083/jcb.143.5.1353
发表时间：
1998-11-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kawahara A;Ohsawa Y;Matsumura H;Uchiyama Y;Nagata S
通讯作者：
Nagata S
影响因子：
5.3
作者：
Schock, Sarah C.;Xu, Jin;Chen, Hsiao-Huei
通讯作者：
Chen, Hsiao-Huei
影响因子：
2.4
作者：
Ahnstedt H;Säveland H;Nilsson O;Edvinsson L
通讯作者：
Edvinsson L