Data from: Evolution of ischemic damage and behavioural deficit over 6 months after MCAo in the rat: selecting the optimal outcomes and statistical power for multi-centre preclinical trials

Key disparities between the timing and methods of assessment in animal stroke studies and clinical trial may be part of the reason for the failure to translate promising findings. This study investigates the development of ischemic damage after thread occlusion MCAo in the rat, using histological and behavioural outcomes. Using the adhesive removal test we investigate the longevity of behavioural deficit after ischemic stroke in rats, and examine the practicality of using such measures as the primary outcome for future studies. Ischemic stroke was induced in 132 Spontaneously Hypertensive Rats which were assessed for behavioural and histological deficits at 1, 3, 7, 14, 21, 28 days, 12 and 24 weeks (n>11 per timepoint). The basic behavioural score confirmed induction of stroke, with deficits specific to stroke animals. Within 7 days, these deficits resolved in 50% of animals. The adhesive removal test revealed contralateral neglect for up to 6 months following stroke. Sample size calculations to facilitate the use of this test as the primary experimental outcome resulted in cohort sizes much larger than are the norm for experimental studies. Histological damage progressed from a necrotic infarct to a hypercellular area that cleared to leave a fluid filled cavity. Whilst absolute volume of damage changed over time, when corrected for changes in hemispheric volume, an equivalent area of damage was lost at all timepoints. Using behavioural measures at chronic timepoints presents significant challenges to the basic science community in terms of the large number of animals required and the practicalities associated with this. Multicentre preclinical randomised controlled trials as advocated by the MultiPART consortium may be the only practical way to deal with this issue.

动物卒中研究与临床试验在评估时机与方法上存在的关键差异，或许是有前景的卒中研究成果无法成功转化的部分诱因。本研究采用组织学与行为学检测指标，探究大鼠经线栓法大脑中动脉闭塞（MCAO）后缺血性损伤的动态演变过程。本研究借助粘胶移除试验，评估大鼠缺血性卒中后行为缺陷的持续时长，并探讨将此类指标作为未来研究首要结局指标的可行性。本研究对132只自发性高血压大鼠（Spontaneously Hypertensive Rats）构建缺血性卒中模型，并在造模后1、3、7、14、21、28天以及12、24周分别对其行为缺陷与组织学损伤进行评估（每个时间点样本量n>11）。基础行为评分证实卒中模型构建成功，卒中组大鼠呈现特异性行为缺陷。造模后7天内，50%的大鼠行为缺陷得到缓解。粘胶移除试验结果显示，卒中后大鼠的对侧忽视症状最长可维持6个月。若将该试验作为首要实验结局指标，所需的队列样本量远高于实验研究的常规标准。组织学损伤呈现动态演化过程：从坏死性梗死灶进展为细胞增生区域，最终该区域被吸收并形成充满液体的空腔。尽管损伤的绝对体积随时间发生变化，但在校正大脑半球体积的波动后，各时间点所损失的等效损伤体积保持一致。在慢性时间点开展行为学检测，会给基础科学研究领域带来显著挑战：不仅需要大量实验动物，还面临相关实操层面的诸多难题。正如MultiPART联盟所倡导的多中心临床前随机对照试验，或许是解决该问题的唯一可行途径。