Laboratory of Experimental Neurology, Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy.
Laboratory of Acute Brain Injury and Therapeutic Strategies, Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy.
Acta Neuropathol Commun. 2021 Apr 26;9(1):76. doi: 10.1186/s40478-021-01165-y.
Post-traumatic epilepsy (PTE) accounts for 5% of all epilepsies and 10-20% of the acquired forms. The latency between traumatic brain injury (TBI) and epilepsy onset in high-risk patients offers a therapeutic window for intervention to prevent or improve the disease course. However, progress towards effective treatments has been hampered by the lack of sensitive prognostic biomarkers of PTE, and of therapeutic targets. There is therefore a pressing clinical need for preclinical PTE models suitable for biomarker discovery and drug testing. We characterized in-depth a model of severe TBI induced by controlled cortical impact evolving into PTE in CD1 adult male mice. To identify sensitive measures predictive of PTE development and severity, TBI mice were longitudinally monitored by video-electrocorticography (ECoG), examined by MRI, and tested for sensorimotor and cognitive deficits and locomotor activity. At the end of the video-ECoG recording mice were killed for brain histological analysis. PTE occurred in 58% of mice with frequent motor seizures (one seizure every other day), as determined up to 5 months post-TBI. The weight loss of PTE mice in 1 week after TBI correlated with the number of spontaneous seizures at 5 months. Moreover, the recovery rate of the sensorimotor deficit detected by the SNAP test before the predicted time of epilepsy onset was significantly lower in PTE mice than in those without epilepsy. Neuroscore, beam walk and cognitive deficit were similar in all TBI mice. The increase in the contusion volume, the volume of forebrain regions contralateral to the lesioned hemisphere and white matter changes over time assessed by MRI were similar in PTE and no-PTE mice. However, brain histology showed a more pronounced neuronal cell loss in the cortex and hippocampus contralateral to the injured hemisphere in PTE than in no-PTE mice. The extensive functional and neuropathological characterization of this TBI model, provides a tool to identify sensitive measures of epilepsy development and severity clinically useful for increasing PTE prediction in high-risk TBI patients. The high PTE incidence and spontaneous seizures frequency in mice provide an ideal model for biomarker discovery and for testing new drugs.
创伤后癫痫（PTE）占所有癫痫的 5%，占获得性癫痫的 10-20%。高危患者创伤性脑损伤（TBI）与癫痫发作之间的潜伏期为干预提供了一个治疗窗口，以预防或改善疾病进程。然而，由于缺乏 PTE 的敏感预后生物标志物和治疗靶点，有效的治疗进展受到了阻碍。因此，迫切需要适合生物标志物发现和药物测试的临床前 PTE 模型。我们深入研究了一种由控制性皮质撞击诱导的严重 TBI 模型，该模型发展为 CD1 成年雄性小鼠的 PTE。为了确定预测 PTE 发展和严重程度的敏感指标，对 TBI 小鼠进行了视频-脑电图（ECoG）的纵向监测，进行了 MRI 检查，并进行了感觉运动和认知缺陷以及运动活动测试。在视频-ECoG 记录结束时，将小鼠处死进行脑组织学分析。在 TBI 后长达 5 个月，通过视频-ECoG 检测到 58%的小鼠出现频繁的运动性癫痫发作（每隔一天一次发作）。TBI 后 1 周 PTE 小鼠的体重减轻与 5 个月时自发性癫痫发作的次数相关。此外，在癫痫发作预测时间之前，通过 SNAP 测试检测到的感觉运动缺陷的恢复率在 PTE 小鼠中明显低于无癫痫小鼠。所有 TBI 小鼠的神经评分、横梁行走和认知缺陷均相似。MRI 评估的挫伤体积增加、损伤半球对侧前脑区域体积和白质变化随时间的变化在 PTE 和非 PTE 小鼠中相似。然而，脑组织学显示，在 PTE 小鼠中，与受伤半球相对应的皮质和海马中的神经元细胞丢失比非 PTE 小鼠更明显。这种 TBI 模型的广泛功能和神经病理学特征提供了一种工具，可以识别癫痫发作发展和严重程度的敏感指标，这对增加高危 TBI 患者的 PTE 预测具有临床意义。在小鼠中 PTE 的高发生率和自发性癫痫发作频率为发现生物标志物和测试新药提供了理想的模型。
Zotero 插件
