title: NKCC1 up-regulation contributes to early post-traumatic seizures and increased post-traumatic seizure susceptibility.
abstract: 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 (GABAA) receptors. The inhibitory activity of GABAAreceptor 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.
authors: 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.|Department of Surgery, Texas A&M University Health Science Center, College of Medicine, Temple, TX, 76504, USA.|Department of Neurosurgery, Neuroscience Institute, Baylor Scott and White Health, Central Division, Temple, TX, 76508, USA.
authors: Fushun
authors: F
authors: Wang
authors: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester, Rochester, NY, 14642, USA.|Neuroscience Graduate Program, University of Rochester, Rochester, NY, 14642, USA.
authors: Xiaowei
authors: X
authors: Wang
authors: Department of Surgery, Texas A&M University Health Science Center, College of Medicine, Temple, TX, 76504, USA. lshapiro@medicine.tamhsc.edu.
authors: Lee A
authors: LA
authors: Shapiro
authors: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester, Rochester, NY, 14642, USA.
authors: Maria L
authors: ML
authors: Cotrina
authors: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester, Rochester, NY, 14642, USA.
authors: Weimin
authors: W
authors: Liu
authors: Department of Neurosurgery, Neuroscience Institute, Baylor Scott and White Health, Central Division, Temple, TX, 76508, USA.
authors: Ernest W
authors: EW
authors: Wang
authors: Nanjing University of Chinese Medicine, Nanjing, 210023, China.
authors: Simeng
authors: S
authors: Gu
authors: Nanjing University of Chinese Medicine, Nanjing, 210023, China.
authors: Wei
authors: W
authors: Wang
authors: Department of Neurosurgery, Xijing Hospital, 4th Military Medical University, Xi'an, China.
authors: Xiaosheng
authors: X
authors: He
authors: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester, Rochester, NY, 14642, USA.
authors: Maiken
authors: M
authors: Nedergaard
authors: Department of Surgery, Texas A&M University Health Science Center, College of Medicine, Temple, TX, 76504, USA. jhuang@sw.org.|Department of Neurosurgery, Neuroscience Institute, Baylor Scott and White Health, Central Division, Temple, TX, 76508, USA. jhuang@sw.org.
authors: Jason H
authors: JH
authors: Huang
mesh_terms: D000641:Ammonia / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D002034:Bumetanide / Q000494:pharmacology; D002452:Cell Count; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004834:Epilepsy, Post-Traumatic / Q000235:genetics* / Q000503:physiopathology; D005071:Evoked Potentials / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D064506:Solute Carrier Family 12, Member 2 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D014851:Wakefulness; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology; D011804:Quinolines
chemical_list: D000641:Ammonia; D002034:Bumetanide; D010751:Phosphopyruvate Hydratase; D011720:Pyrazoles; D011758:Pyrroles; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064506:Solute Carrier Family 12, Member 2; D005680:gamma-Aminobutyric Acid; C506615:HTS 466284; D011804:Quinolines; C578878:Slc12a2 protein, mouse
keywords: Bumetanide; In vivo electrophysiology; TGF; Traumatic brain injury