Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, United States of America.
Departamento de Fisiologia, Laboratório de Neurofisiologia, Universidade Federal de São Paulo, UNIFESP, São Paulo, Brazil.
PLoS One. 2023 Jul 13;18(7):e0288363. doi: 10.1371/journal.pone.0288363. eCollection 2023.
The pathophysiological changes that occur after traumatic brain injury (TBI) can lead to the development of post-traumatic epilepsy, a life-long complication of brain trauma. The etiology of post-traumatic epilepsy remains unknown, but TBI brains exhibit an abnormal excitatory / inhibitory balance. In this study, we examine how brain injury alters susceptibility to chemically-induced seizures in C57Bl/6J mice, and if pharmacological enhancement of glutamate transporters can reduce chronic post-traumatic seizures. We found that controlled cortical impact (CCI) mice display delayed susceptibility to pentylenetetrazol (PTZ)-induced seizures. While CCI mice have no change in seizure susceptibility at 7d post-injury (dpi), at 70dpi they have reduced latency to PTZ-induced seizure onset, higher seizure frequency and longer seizure duration. Quantification of glutamate transporter mRNA showed that levels of Scl1a2 and Scl1a3 mRNA were increased at 7dpi, but significantly decreased at 70dpi. To test if increased levels of glutamate transporters can ameliorate delayed-onset seizure susceptibility in TBI mice, we exposed a new cohort of mice to CCI and administered ceftriaxone (200mg/kg/day) for 14d from 55-70dpi. We found that ceftriaxone significantly increased Scl1a2 and Scl1a3 in CCI mouse brain at 70dpi, and prevented the susceptibility of CCI mice to PTZ-induced seizures. This study demonstrates cortical impact can induce a delayed-onset seizure phenotype in mice. Delayed (55dpi) ceftriaxone treatment enhances glutamate transporter mRNA in the CCI brain, and reduces PTZ-induced seizures in CCI mice.
颅脑创伤（TBI）后发生的病理生理变化可导致外伤性癫痫的发生，这是脑外伤的终身并发症。外伤性癫痫的病因尚不清楚，但 TBI 大脑表现出异常的兴奋/抑制平衡。在这项研究中，我们研究了脑损伤如何改变 C57Bl/6J 小鼠对化学诱导性癫痫发作的易感性，以及增强谷氨酸转运体的药理学是否可以减少慢性创伤后癫痫发作。我们发现，皮质控制冲击（CCI）小鼠对戊四氮（PTZ）诱导的癫痫发作显示出延迟的易感性。虽然 CCI 小鼠在损伤后 7d（dpi）时没有改变癫痫易感性，但在 70dpi 时，它们对 PTZ 诱导的癫痫发作起始的潜伏期缩短，癫痫发作频率增加，癫痫发作持续时间延长。谷氨酸转运体 mRNA 的定量显示，Scl1a2 和 Scl1a3 mRNA 的水平在 7dpi 时增加，但在 70dpi 时显著降低。为了测试增加的谷氨酸转运体水平是否可以改善 TBI 小鼠延迟发作的癫痫易感性，我们使另一批小鼠经受 CCI，并从 55-70dpi 每天给予头孢曲松（200mg/kg）治疗 14d。我们发现，头孢曲松在 70dpi 时显著增加了 CCI 小鼠大脑中的 Scl1a2 和 Scl1a3，并防止了 CCI 小鼠对 PTZ 诱导的癫痫发作的易感性。这项研究表明皮质冲击可在小鼠中诱导延迟发作的癫痫表型。延迟（55dpi）头孢曲松治疗可增强 CCI 大脑中的谷氨酸转运体 mRNA，并减少 CCI 小鼠中 PTZ 诱导的癫痫发作。
