Data_Sheet_1_Bridging the Transient Intraluminal Stroke Preclinical Model to Clinical Practice: From Improved Surgical Procedures to a Workflow of Functional Tests.docx

Acute ischemic stroke (AIS) remains a leading cause of mortality, despite significant advances in therapy (endovascular thrombectomy). Failure in developing novel effective therapies is associated with unsuccessful translation from preclinical studies to clinical practice, associated to inconsistent and highly variable infarct areas and lack of relevant post-stroke functional evaluation in preclinical research. To outreach these limitations, we optimized the intraluminal transient middle cerebral occlusion, a widely used mouse stroke model, in two key parameters, selection of appropriate occlusion filaments and time of occlusion, which show a significant variation in the literature. We demonstrate that commercially available filaments with short coating length (1–2 mm), together with 45-min occlusion, results in a consistent affected brain region, similar to what is observed in most patients with AIS. Importantly, a dedicated post-stroke care protocol, based on clinical practice applied to patients who had stroke, resulted in lower mortality and improved mice welfare. Finally, a battery of tests covering relevant fine motor skills, sensory functions, and learning/memory behaviors revealed a significant effect of tMCAO brain infarction, which is parallel to patient symptomatology as measured by relevant clinical scales (NIH Stroke Scale, NIHSS and modified Rankin Scale, mRS). Thus, in order to enhance translation to clinical practice, future preclinical stroke research must consider the methodology described in this study, which includes improved reproducible surgical procedure, postoperative care, and the battery of functional tests. This will be a major step s closing the gap from bench to bedside, rendering the development of novel effective therapeutic approaches.

急性缺血性卒中（AIS）尽管在治疗（如血管内血栓切除术）方面取得了显著进展，但依然是导致死亡的主要原因。新型有效疗法的开发失败，与其从临床前研究向临床实践的转化不成功有关，这种转化受到不统一且高度可变性的梗死区域以及临床前研究中缺乏相关卒中后功能评估的影响。为了克服这些限制，我们对广泛使用的鼠类卒中模型——经皮腔内暂时性中脑动脉闭塞（tMCAO），在两个关键参数上进行了优化，即合适的闭塞纤维选择和闭塞时间，这两个参数在文献中存在显著差异。我们证明了具有短涂层长度（1-2毫米）的商业可用纤维，结合45分钟的闭塞，导致一致的受影响脑区，这与大多数急性缺血性卒中患者观察到的情况相似。重要的是，基于临床实践应用于卒中患者的专用卒中后护理方案，导致了较低的死亡率并改善了小鼠福利。最后，一系列涵盖相关精细运动技能、感觉功能和学习/记忆行为的测试，揭示了tMCAO脑梗死具有显著影响，这与通过相关临床量表（美国国立卫生研究院卒中量表、NIHSS和改良Rankin量表、mRS）测量的患者症状学平行。因此，为了加强临床转化，未来的临床前卒中研究必须考虑本研究所描述的方法，包括改进的可重复手术程序、术后护理和功能测试系列。这将是一步重要的跨越，缩小了从实验室到病床的差距，从而促进了新型有效治疗方法的开发。