Drieu Antoine, Buendia Izaskun, Levard Damien, Hélie Pauline, Brodin Camille, Vivien Denis, Rubio Marina
Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, Cyceron, 14000 Caen, France, Normandie Université, 14000, Caen, France.
Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria, Madrid, Spain.
Transl Stroke Res. 2020 Jun;11(3):481-495. doi: 10.1007/s12975-019-00733-8. Epub 2019 Sep 14.
The poor clinical relevance of experimental models of stroke contributes to the translational failure between preclinical and clinical studies testing anti-inflammatory molecules for ischemic stroke. Here, we (i) describe the time course of inflammatory responses triggered by a thromboembolic model of ischemic stroke and (ii) we examine the efficacy of two clinically tested anti-inflammatory drugs: Minocycline or anti-CD49d antibodies (tested in stroke patients as Natalizumab) administered early (1 h) or late (48 h) after stroke onset. Radiological (lesion volume) and neurological (grip test) outcomes were evaluated at 24 h and 5 days after stroke. Immune cell responses peaked 48 h after stroke onset. Myeloid cells (microglia/macrophages, dendritic cells, and neutrophils) were already increased 24 h after stroke onset, peaked at 48 h, and remained increased-although to a lesser extent-5 days after stroke onset. CD8 and CD4 T-lymphocytes infiltrated the ipsilateral hemisphere later on (only from 48 h). These responses occurred together with a progressive blood-brain barrier leakage at the lesion site, starting 24 h after stroke onset. Lesion volume was maximal 24-48 h after stroke onset. Minocycline reduced both lesion volume and neurological deficit only when administered early after stroke onset. The blockade of leukocyte infiltration by anti-CD49d had no impact on lesion volume or long-term neurological deficit, independently of the timing of treatment. Our data are in accordance with the results of previous clinical reports on the use of Minocycline and Natalizumab on ischemic stroke. We thus propose the use of this clinically relevant model of thromboembolic stroke with recanalization for future testing of anti-inflammatory strategies for stroke.
中风实验模型较差的临床相关性导致了在针对缺血性中风测试抗炎分子的临床前研究和临床研究之间的转化失败。在此，我们（i）描述了由缺血性中风的血栓栓塞模型引发的炎症反应的时间进程，并且（ii）我们研究了两种经过临床测试的抗炎药物的疗效：米诺环素或抗CD49d抗体（在中风患者中作为那他珠单抗进行测试）在中风发作后早期（1小时）或晚期（48小时）给药。在中风后24小时和5天时评估放射学（病变体积）和神经学（握力测试）结果。免疫细胞反应在中风发作后48小时达到峰值。髓样细胞（小胶质细胞/巨噬细胞、树突状细胞和中性粒细胞）在中风发作后24小时就已经增加，在48小时达到峰值，并在中风发作后5天仍保持增加，尽管程度较小。CD8和CD4 T淋巴细胞随后浸润同侧半球（仅从48小时开始）。这些反应与病变部位血脑屏障的渐进性渗漏同时发生，从中风发作后24小时开始。病变体积在中风发作后24 - 48小时最大。米诺环素仅在中风发作后早期给药时才会减少病变体积和神经功能缺损。抗CD49d对白细胞浸润的阻断对病变体积或长期神经功能缺损没有影响，与治疗时间无关。我们的数据与先前关于米诺环素和那他珠单抗用于缺血性中风的临床报告结果一致。因此，我们建议使用这种具有再通的血栓栓塞性中风的临床相关模型，用于未来中风抗炎策略的测试。
