J147 Reduces tPA-Induced Brain Hemorrhage in Acute Experimental Stroke in Rats.
J147 Reduces tPA-Induced Brain Hemorrhage in Acute Experimental Stroke in Rats.
复制标题
DOI：
10.3389/fneur.2022.821082
复制
发表时间：
2022
影响因子：
3.4
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Jin R;Wang M;Zhong W;Kissinger CR;Villafranca JE;Li G
J147是一种新型神经营养化合物，最初被开发用于治疗与衰老相关的神经系统疾病。基于该化合物所表现出的广谱细胞保护作用，我们研究了J147是否对急性缺血性卒中具有脑保护作用，以及它是否能增强组织纤溶酶原激活剂（tPA）溶栓治疗的有效性。采用腔内缝合线或栓塞性大脑中动脉闭塞（eMCAO）对大鼠进行短暂性大脑中动脉闭塞（tMCAO），并单独或联合tPA静脉注射J147。我们发现J147治疗显著减少脑卒中后2小时给药的tMCAO模型的梗死体积，但没有tPA的eMCAO没有效果。然而，在eMCAO模型中，与生理盐水或tPA单独组相比，J147加tPA在卒中发作后4小时联合治疗可显著减少卒中后72小时的梗死体积和神经功能缺损。重要的是，联合治疗显著减少延迟tpa相关的脑出血和继发性微血管血栓形成。这些保护作用与j147介导的基质金属蛋白酶-9 （MMP9）、15-脂氧合酶-1和纤溶酶原激活物抑制剂（PAI）在缺血半球（主要是缺血脑内皮）表达的抑制有关。此外，与单独使用生理盐水或tPA组相比，联合治疗在卒中后24小时显著降低了循环血小板活化和血小板-白细胞聚集，这也可能有助于减少微血管血栓形成和神经炎症（如减少中性粒细胞脑浸润和小胶质细胞活化）。我们的研究结果表明，在急性缺血性脑卒中缝合模型中，J147单独治疗具有脑细胞保护作用，而在栓塞性脑卒中模型中，J147与tPA合用可减少tPA诱导的延迟性脑出血，并具有脑保护作用。这些发现提示J147-tPA联合治疗可能是改善缺血性脑卒中治疗的一种有希望的方法。
J147, a novel neurotrophic compound, was originally developed to treat aging-associated neurological diseases. Based on the broad spectrum of cytoprotective effects exhibited by this compound, we investigated whether J147 has cerebroprotection for acute ischemic stroke and whether it can enhance the effectiveness of thrombolytic therapy with tissue plasminogen activator (tPA). Rats were subjected to transient occlusion of the middle cerebral artery (tMCAO) by insertion of an intraluminal suture or embolic middle cerebral artery occlusion (eMCAO), and treated intravenously with J147 alone or in combination with tPA. We found that J147 treatment significantly reduced infarct volume when administered at 2 h after stroke onset in the tMCAO model, but had no effect in eMCAO without tPA. However, combination treatment with J147 plus tPA at 4 h after stroke onset significantly reduced infarct volume and neurological deficits at 72 h after stroke compared with saline or tPA alone groups in the eMCAO model. Importantly, the combination treatment significantly reduced delayed tPA-associated brain hemorrhage and secondary microvascular thrombosis. These protective effects were associated with J147-mediated inhibition of matrix metalloproteinase-9 (MMP9), 15-lipoxygenase-1, and plasminogen activator inhibitor (PAI) expression in the ischemic hemispheres (predominantly in ischemic cerebral endothelium). Moreover, the combination treatment significantly reduced circulating platelet activation and platelet-leukocyte aggregation compared with saline or tPA alone groups at 24 h after stroke, which might also contribute to reduced microvascular thrombosis and neuroinflammation (as demonstrated by reduced neutrophil brain infiltration and microglial activation). Our results demonstrate that J147 treatment alone exerts cerebral cytoprotective effects in a suture model of acute ischemic stroke, while in an embolic stroke model co-administration of J147 with tPA reduces delayed tPA-induced intracerebral hemorrhage and confers cerebroprotection. These findings suggest that J147-tPA combination therapy could be a promising approach to improving the treatment of ischemic stroke.
登录
查看更多内容
DOI：
10.3390/molecules15031168
发表时间：
2010-03-03
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Duncan RS;Goad DL;Grillo MA;Kaja S;Payne AJ;Koulen P
通讯作者：
Koulen P
DOI：
10.18632/aging.100838
发表时间：
2015-11
期刊：
Aging
影响因子：
--
作者：
Currais A;Goldberg J;Farrokhi C;Chang M;Prior M;Dargusch R;Daugherty D;Armando A;Quehenberger O;Maher P;Schubert D
通讯作者：
Schubert D
影响因子：
8.3
作者：
Jin R;Xiao AY;Chen R;Granger DN;Li G
通讯作者：
Li G
影响因子：
4.3
作者：
Li, Jianxin;Chen, Ling;Yu, Yingcong
通讯作者：
Yu, Yingcong
影响因子：
3.7
作者：
Chen Q;Prior M;Dargusch R;Roberts A;Riek R;Eichmann C;Chiruta C;Akaishi T;Abe K;Maher P;Schubert D
通讯作者：
Schubert D