Jin Rong, Wang Min, Zhong Wei, Kissinger Charles R, Villafranca J Ernest, Li Guohong
Department of Neurosurgery and Neuroscience Institute, Penn State Hershey Medical Center, Hershey, PA, United States.
Abrexa Pharmaceticals, Inc., San Diego, CA, United States.
Front Neurol. 2022 Mar 2;13:821082. doi: 10.3389/fneur.2022.821082. eCollection 2022.
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.
新型神经营养化合物J147最初是为治疗与衰老相关的神经疾病而研发。基于该化合物所展现出的广泛细胞保护作用，我们研究了J147对急性缺血性中风是否具有脑保护作用，以及它是否能增强组织型纤溶酶原激活剂（tPA）溶栓治疗的效果。
通过插入腔内缝线使大鼠大脑中动脉短暂闭塞（tMCAO）或进行栓塞性大脑中动脉闭塞（eMCAO），然后单独静脉注射J147或联合tPA进行治疗。
我们发现，在tMCAO模型中，中风发作后2小时给予J147治疗可显著减少梗死体积，但在未使用tPA的eMCAO模型中则无效果。然而，在eMCAO模型中，中风发作后4小时联合使用J147和tPA治疗与单独使用生理盐水或tPA组相比，在中风后72小时可显著减少梗死体积和神经功能缺损。重要的是，联合治疗可显著减少tPA相关的延迟性脑出血和继发性微血管血栓形成。这些保护作用与J147介导的缺血半球（主要是缺血性脑内皮）中基质金属蛋白酶-9（MMP9）、15-脂氧合酶-1和纤溶酶原激活物抑制剂（PAI）表达的抑制有关。此外，与单独使用生理盐水或tPA组相比，联合治疗在中风后24小时可显著减少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（表现为中性粒细胞脑浸润和小胶质细胞活化减少）。
我们的结果表明，单独使用J147治疗在急性缺血性中风的缝线模型中发挥脑保护作用，而在栓塞性中风模型中，J147与tPA联合使用可减少tPA诱导的延迟性脑出血并提供脑保护。这些发现表明，J147-tPA联合治疗可能是改善缺血性中风治疗的一种有前景的方法。
