Normandie Univ, UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain @Caen-Normandie (BB@C), UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Caen, France.
Normandie Univ, UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain @Caen-Normandie (BB@C), UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Caen, France; CHU Caen, Department of Clinical Research, Caen University Hospital, Avenue de la Côte de Nacre, Caen, France.
Brain Behav Immun. 2021 Jan;91:649-667. doi: 10.1016/j.bbi.2020.09.025. Epub 2020 Oct 2.
For the last two decades, researchers have placed hopes in a new era in which a combination of reperfusion and neuroprotection would revolutionize the treatment of stroke. Nevertheless, despite the thousands of papers available in the literature showing positive results in preclinical stroke models, randomized clinical trials have failed to show efficacy. It seems clear now that the existing data obtained in preclinical research have depicted an incomplete picture of stroke pathophysiology. In order to ameliorate bench-to-bed translation, in this review we first describe the main actors on stroke inflammatory and immune responses based on the available preclinical data, highlighting the fact that the link between leukocyte infiltration, lesion volume and neurological outcome remains unclear. We then describe what is known on neuroinflammation and immune responses in stroke patients, and summarize the results of the clinical trials on immunomodulatory drugs. In order to understand the gap between clinical trials and preclinical results on stroke, we discuss in detail the experimental results that served as the basis for the summarized clinical trials on immunomodulatory drugs, focusing on (i) experimental stroke models, (ii) the timing and selection of outcome measuring, (iii) alternative entry routes for leukocytes into the ischemic region, and (iv) factors affecting stroke outcome such as gender differences, ageing, comorbidities like hypertension and diabetes, obesity, tobacco, alcohol consumption and previous infections like Covid-19. We can do better for stroke treatment, especially when targeting inflammation following stroke. We need to re-think the design of stroke experimental setups, notably by (i) using clinically relevant models of stroke, (ii) including both radiological and neurological outcomes, (iii) performing long-term follow-up studies, (iv) conducting large-scale preclinical stroke trials, and (v) including stroke comorbidities in preclinical research.
在过去的二十年中，研究人员一直寄希望于一个新时代的到来，即再灌注和神经保护的结合将彻底改变中风的治疗方法。然而，尽管文献中有数千篇论文显示出在临床前中风模型中取得了积极的结果，但随机临床试验未能显示出疗效。现在似乎很清楚，现有的临床前研究数据描绘了中风病理生理学的不完整画面。为了改善从实验室到病床的转化，在这篇综述中，我们首先根据现有的临床前数据描述了中风炎症和免疫反应的主要参与者，强调了白细胞浸润、病变体积和神经功能结局之间的联系仍然不清楚这一事实。然后，我们描述了中风患者的神经炎症和免疫反应的已知情况，并总结了免疫调节药物的临床试验结果。为了了解中风的临床试验和临床前结果之间的差距，我们详细讨论了作为免疫调节药物总结临床试验基础的实验结果，重点关注：（i）实验性中风模型；（ii）结果测量的时间和选择；（iii）白细胞进入缺血区域的替代进入途径；以及（iv）影响中风结局的因素，如性别差异、衰老、高血压和糖尿病等合并症、肥胖、吸烟、饮酒和以前的感染如新冠病毒。我们可以为中风治疗做得更好，尤其是当针对中风后的炎症时。我们需要重新思考中风实验设置的设计，特别是通过：（i）使用临床相关的中风模型；（ii）包括放射学和神经学结果；（iii）进行长期随访研究；（iv）进行大规模的临床前中风试验；以及（v）在临床前研究中纳入中风合并症。
