Translational Neurosurgery and Neurobiology, Department of Neurosurgery, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Department of Neurosurgery, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Eur Surg Res. 2023;64(1):120-138. doi: 10.1159/000524432. Epub 2022 Apr 6.
Animal models for preclinical research of subarachnoid hemorrhage (SAH) are widely used as much of the pathophysiology remains unknown. However, the burden of these models inflicted on the animals is not well characterized. The European directive requires severity assessment-based allocation to categories. Up to now, the classification into predefined categories is rather subjective and often without underlying scientific knowledge. We therefore aimed at assessing the burden of rats after SAH or the corresponding sham surgery to provide a scientific assessment.
We performed a multimodal approach, using different behavior tests, clinical and neurological scoring, and biochemical markers using the common model for SAH of intracranial endovascular filament perforation in male Wistar rats. Up to 7 days after surgery, animals with SAH were compared to sham surgery and to a group receiving only anesthesia and analgesia.
Sham surgery (n = 15) and SAH (n = 16) animals showed an increase in the clinical score the first days after surgery, indicating clinical deterioration, while animals receiving only anesthesia without surgery (n = 5) remained unaffected. Body weight loss occurred in all groups but was more pronounced and statistically significant only after surgery. The analysis of burrowing, open field (total distance, erections), balance beam, and neuroscore showed primarily an effect of the surgery itself in sham surgery and SAH animals. Only concerning balance beam and neuroscore, a difference was visible between sham surgery and SAH. The outcome of the analysis of systemic and local inflammatory parameters and of corticosterone in blood and its metabolites in feces was only robust in animals suffering from larger bleedings. Application of principal component analysis resulted in a clear separation of sham surgery and SAH animals from their respective baseline as well as from the anesthesia-only group at days 1 and 3, with the difference between sham surgery and SAH being not significant.
DISCUSSION/CONCLUSION: To our knowledge, we are the first to publish detailed clinical score sheet data combined with advanced behavioral assessment in the endovascular perforation model for SAH in rats. The tests chosen here clearly depict an impairment of the animals within the first days after surgery and are consequently well suited for assessment of the animals' suffering in the model. A definitive classification into one of the severity categories named by the EU directive is yet pending and has to be performed in the future by including the assessment data from different neurological and nonneurological disease models.
蛛网膜下腔出血（SAH）的临床前研究中广泛使用动物模型，因为其病理生理学仍有许多未知之处。然而，这些模型给动物带来的负担并没有得到很好的描述。欧洲指令要求基于严重程度评估进行分类。到目前为止，将其分类为预设类别是相当主观的，而且通常没有基础的科学知识。因此，我们旨在评估 SAH 或相应的假手术后大鼠的负担，以提供科学评估。
我们采用多模态方法，使用不同的行为测试、临床和神经评分以及使用颅内血管内纤维穿孔的常见 SAH 模型的生化标志物，对雄性 Wistar 大鼠进行研究。在手术后 7 天内，将 SAH 动物与假手术和仅接受麻醉和镇痛的动物进行比较。
假手术（n=15）和 SAH（n=16）动物在手术后的最初几天内临床评分增加，表明临床恶化，而仅接受手术而未接受手术的动物（n=5）则不受影响。所有组都出现了体重减轻，但仅在手术后更明显且具有统计学意义。挖洞、旷场（总距离、勃起）、平衡木和神经评分的分析主要显示假手术和 SAH 动物的手术本身的影响。只有在平衡木和神经评分方面，假手术和 SAH 之间存在差异。全身和局部炎症参数以及血液中的皮质酮及其粪便代谢物的分析结果仅在出血较大的动物中表现稳健。主成分分析的应用导致在第 1 天和第 3 天，假手术和 SAH 动物与其各自的基线以及仅接受麻醉的动物清晰分离，假手术和 SAH 之间的差异无统计学意义。
讨论/结论：据我们所知，我们是第一组在大鼠血管内穿孔蛛网膜下腔出血模型中发表详细临床评分表数据并结合先进行为评估的人。这里选择的测试清楚地描绘了手术后最初几天内动物的受损情况，因此非常适合评估模型中动物的痛苦。要对其进行明确分类，需要将其归入欧盟指令命名的严重程度类别之一，未来需要通过包括来自不同神经和非神经疾病模型的评估数据来完成。
