Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107 2020, Lebanon.
Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Hadath P.O. Box 6573/14, Lebanon.
Int J Mol Sci. 2021 Jun 16;22(12):6456. doi: 10.3390/ijms22126456.
Post-traumatic epilepsy (PTE) and neurocognitive deficits are devastating sequelae of head injuries that are common in adolescents. Investigating desperately needed treatments is hindered by the difficulties in inducing PTE in rodents and the lack of established immature rat models of pediatric PTE. Hemorrhage is a significant risk factor for PTE, but compared to humans, rats are less prone to bleeding because of their rapid blood coagulation system. In this study, we promoted bleeding in the controlled cortical impact (CCI) closed-head injury model with a 20 min pre-impact 600 IU/kg intraperitoneal heparin injection in postnatal day 35 (P35) periadolescent rats, given the preponderance of such injuries in this age group. Temporo-parietal CCI was performed post-heparin (HTBI group) or post-saline (TBI group). Controls were subjected to sham procedures following heparin or saline administration. Continuous long-term EEG monitoring was performed for 3 months post-CCI. Sensorimotor testing, the Morris water maze, and a modified active avoidance test were conducted between P80 and P100. Glial fibrillary acidic protein (GFAP) levels and neuronal damage were also assessed. Compared to TBI rats, HTBI rats had persistently higher EEG spiking and increased hippocampal GFAP levels ( < 0.05). No sensorimotor deficits were detected in any group. Compared to controls, both HTBI and TBI groups had a long-term hippocampal neuronal loss ( < 0.05), as well as contextual and visuospatial learning deficits ( < 0.05). The hippocampal astrogliosis and EEG spiking detected in all rats subjected to our hemorrhage-promoting procedure suggest the emergence of hyperexcitable networks and pave the way to a periadolescent PTE rat model.
创伤后癫痫（PTE）和神经认知缺陷是青少年常见的颅脑损伤的毁灭性后遗症。由于难以在啮齿动物中诱发 PTE 以及缺乏已建立的儿科 PTE 未成年大鼠模型，因此迫切需要进行治疗研究。出血是 PTE 的一个重要危险因素，但与人类相比，由于其快速的凝血系统，大鼠不太容易出血。在这项研究中，我们在出生后第 35 天（P35）的青春期前大鼠中使用 20 分钟的腹腔内肝素注射（600 IU/kg）来促进控制皮质撞击（CCI）闭合性颅脑损伤模型中的出血，因为这个年龄段此类损伤更为普遍。在肝素后（HTBI 组）或盐水后（TBI 组）进行颞顶叶 CCI。对照组在肝素或盐水给药后接受假手术。在 CCI 后进行连续长期 EEG 监测 3 个月。在 P80 至 P100 期间进行感觉运动测试、Morris 水迷宫和改良主动回避测试。还评估了神经胶质纤维酸性蛋白（GFAP）水平和神经元损伤。与 TBI 大鼠相比，HTBI 大鼠的 EEG 尖峰持续升高，海马 GFAP 水平升高（<0.05）。在任何组中都未检测到感觉运动缺陷。与对照组相比，HTBI 和 TBI 组均有长期的海马神经元丢失（<0.05），以及情景和空间学习缺陷（<0.05）。所有接受我们促出血程序的大鼠均检测到海马星形胶质增生和 EEG 尖峰，这表明兴奋性网络的出现，并为青春期前 PTE 大鼠模型铺平了道路。
