Wang Fushun, Wang Xiaowei, Shapiro Lee A, Cotrina Maria L, Liu Weimin, Wang Ernest W, Gu Simeng, Wang Wei, He Xiaosheng, Nedergaard Maiken, Huang Jason H
Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester, Rochester, NY, 14642, USA.
Brain Struct Funct. 2017 Apr;222(3):1543-1556. doi: 10.1007/s00429-016-1292-z. Epub 2016 Sep 1.
Traumatic brain injury (TBI) is not only a leading cause for morbidity and mortality in young adults (Bruns and Hauser, Epilepsia 44(Suppl 10):210, 2003), but also a leading cause of seizures. Understanding the seizure-inducing mechanisms of TBI is of the utmost importance, because these seizures are often resistant to traditional first- and second-line anti-seizure treatments. The early post-traumatic seizures, in turn, are a contributing factor to ongoing neuropathology, and it is critically important to control these seizures. Many of the available anti-seizure drugs target gamma-aminobutyric acid (GABA) receptors. The inhibitory activity of GABA receptor activation depends on low intracellular Cl, which is achieved by the opposing regulation of Na-K-Cl cotransporter 1 (NKCC1) and K-Cl-cotransporter 2 (KCC2). Up-regulation of NKCC1 in neurons has been shown to be involved in neonatal seizures and in ammonia toxicity-induced seizures. Here, we report that TBI-induced up-regulation of NKCC1 and increased intracellular Cl concentration. Genetic deletion of NKCC1 or pharmacological inhibition of NKCC1 with bumetanide suppresses TBI-induced seizures. TGFβ expression was also increased after TBI and competitive antagonism of TGFβ reduced NKKC1 expression, ameliorated reactive astrocytosis, and inhibited seizures. Thus, TGFβ might be an important pathway involved in NKCC1 up-regulation after TBI. Our findings identify neuronal up-regulation of NKCC1 and its mediation by TGFβ, as a potential and important mechanism in the early post-traumatic seizures, and demonstrate the therapeutic potential of blocking this pathway.
创伤性脑损伤（TBI）不仅是年轻成年人发病和死亡的主要原因（Bruns和Hauser，《癫痫》44（增刊10）：210，2003），也是癫痫发作的主要原因。了解TBI诱发癫痫的机制至关重要，因为这些癫痫通常对传统的一线和二线抗癫痫治疗有抗性。创伤后早期癫痫发作反过来又是持续神经病理学的一个促成因素，控制这些癫痫发作至关重要。许多现有的抗癫痫药物靶向γ-氨基丁酸（GABA）受体。GABA受体激活的抑制活性取决于低细胞内氯离子浓度，这是通过钠-钾-氯共转运体1（NKCC1）和钾-氯共转运体2（KCC2）的反向调节实现的。神经元中NKCC1的上调已被证明与新生儿癫痫发作和氨毒性诱导的癫痫发作有关。在此，我们报告TBI诱导NKCC1上调并增加细胞内氯离子浓度。NKCC1的基因缺失或用布美他尼对NKCC1进行药理学抑制可抑制TBI诱导的癫痫发作。TBI后TGFβ表达也增加，TGFβ的竞争性拮抗作用降低了NKKC1表达，改善了反应性星形胶质细胞增生，并抑制了癫痫发作。因此，TGFβ可能是TBI后NKCC1上调所涉及的一条重要途径。我们的研究结果确定了神经元中NKCC1的上调及其由TGFβ介导，这是创伤后早期癫痫发作的一个潜在且重要的机制，并证明了阻断该途径的治疗潜力。
