Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University, Munich, Germany.
Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
Epilepsia. 2018 Apr;59(4):765-777. doi: 10.1111/epi.14028. Epub 2018 Feb 26.
Rodent epilepsy models can significantly contribute to our understanding of pathophysiological mechanisms and to validation of biomarker and target candidates. Evidence-based severity assessment is a presupposition for the ethical evaluation of animal experimentation allowances as well as for the development of efficacious refinement concepts.
Aiming to improve our understanding of the impact of experimental procedures and repeated seizures, we have completed a comprehensive behavioral and biochemical analysis assessing various parameters that can inform about the influence of an electrical kindling paradigm on well-being in rats. Thereby, we have focused on the immediate effects of phases with focal and generalized seizures with behavioral testing during kindling acquisition.
Electrode implantation exerted mild effects on anxiety-associated behavior and reduced serum corticosterone at 3 weeks, but not 7 weeks, following surgery. Analysis in kindled rats excluded any relevant impact of focal seizures on behavioral and biochemical parameters. Assessment in rats with generalized seizures revealed an impact on nest complexity scores, nest soiling, and selected parameters in paradigms evaluating anxiety-associated behavior. Moreover, serum corticosterone levels, but neither hair corticosterone nor fecal corticosterone metabolite concentrations were lowered as a consequence of repeated generalized seizures. The assessment of various other behavioral and biochemical parameters did not reveal any other relevant effects of generalized seizures. Cross-correlation analysis suggested that assessment of nest building and maintenance can provide information comparable to that from more elaborate behavioral assays. This finding provides first evidence that nest scoring might serve as a simple and valid approach to evaluate rat well-being during routine assessment schemes.
The findings argue against a persistent level of pronounced distress and suggest a classification of the kindling paradigm as a model with moderate severity based on a longer-lasting mild impact on animal behavioral patterns. This suggestion provides a basis for a prospective and retrospective case-by-case severity assessment.
啮齿动物癫痫模型可以极大地帮助我们理解病理生理机制，并验证生物标志物和靶标候选物。基于证据的严重程度评估是动物实验允许的伦理评估以及有效改进概念的发展的前提。
为了提高我们对实验程序和反复癫痫发作影响的理解，我们完成了一项全面的行为和生化分析，评估了各种参数，这些参数可以提供有关电点燃范式对大鼠健康影响的信息。因此，我们专注于在获得点燃过程中通过行为测试来研究焦点和全身性癫痫发作的即时影响。
电极植入对焦虑相关行为产生了轻微影响，并在手术后 3 周而不是 7 周时降低了血清皮质酮。在点燃的大鼠中分析排除了焦点性癫痫对行为和生化参数的任何相关影响。在全身性癫痫发作的大鼠中评估发现，全身性癫痫发作对巢复杂度评分、巢污染以及评估焦虑相关行为的范式中的某些参数有影响。此外，反复全身性癫痫发作并未降低血清皮质酮水平，也未降低毛发皮质酮或粪便皮质酮代谢物浓度。评估其他各种行为和生化参数未发现全身性癫痫发作的其他相关影响。交叉相关分析表明，评估巢的建造和维护可以提供与更复杂行为测定相当的信息。这一发现首次表明，巢评分可能是在常规评估方案中评估大鼠健康的一种简单而有效的方法。
这些发现反对持续存在明显痛苦的水平，并表明基于对动物行为模式的持久轻度影响，点燃范式被归类为中度严重程度的模型。这一建议为前瞻性和回顾性的逐个病例严重程度评估提供了基础。
