title: Inhibition of Na(+)-K(+)-2Cl(-) Cotransporter-1 attenuates traumatic brain injury-induced neuronal apoptosis via regulation of Erk signaling.
abstract: Traumatic brain injury (TBI) is the leading cause of mortality and morbidity worldwide and is characterized by immediate brain damage and secondary injuries, such as brain edema and ischemia. However, the exact pathological mechanisms that comprise these associated secondary injuries have not been fully elucidated. This study aimed to investigate the role of the Na(+)-K(+)-2Cl(-) cotransporter-1 (NKCC1) in the disruption of ion homeostasis and neuronal apoptosis in TBI. Using a traumatic neuron injury (TNI) model in vitro and a controlled cortex injury (CCI) model in vivo, the present study investigated changes in the expression and effects of NKCC1 in TBI using western blot, RNA interference, a lactate dehydrogenase (LDH) release assay, TdT-mediated dUTP Nick end-labeling (TUNEL) analysis, sodium imaging, brain water content, and neurological severity scoring. TBI induced the expression of NKCC1 to be significantly upregulated in the cortex, both in vitro and in vivo. Pharmacological inhibitor bumetanide (Bume) or NKCC1 RNA interference significantly attenuated TBI-induced intracellular Na(+) increase, inhibited neuronal apoptosis, and improved brain edema and neurological function. Furthermore, NKCC1 inhibition also significantly inhibited TBI-induced extracellular signal-regulated kinase (Erk) activation. Erk inhibition significantly protected neurons from TBI injury; however, Erk inhibition had no effect on NKCC1 expression or the neuroprotective effect of NKCC1 inhibition against TBI. This study demonstrates the role of NKCC1 in TBI-induced brain cortex injury, establishing that NKCC1 may play a neurotoxic role in TBI and that the inhibition of NKCC1 may protect neurons from TBI via the regulation of Erk signaling.
authors: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors: Hao
authors: H
authors: Hui
authors: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors: Wei
authors: W
authors: Rao
authors: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors: Lei
authors: L
authors: Zhang
authors: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors: Zhen
authors: Z
authors: Xie
authors: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors: Cheng
authors: C
authors: Peng
authors: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors: Ning
authors: N
authors: Su
authors: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors: Kai
authors: K
authors: Wang
authors: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors: Li
authors: L
authors: Wang
authors: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors: Peng
authors: P
authors: Luo
authors: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors: Ye-lu
authors: YL
authors: Hao
authors: Department of Neurosurgery, Affiliated Hospital of Logistics, University of Chinese Armed Police Forces, Chenglin Road, Tianjin 300162, PR China. Electronic address: zhangsai718@vip.126.com.
authors: Sai
authors: S
authors: Zhang
authors: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China. Electronic address: feizhou@fmmu.edu.cn.
authors: Zhou
authors: Z
authors: Fei
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D000070642:Brain Injuries, Traumatic / Q000378:metabolism* / Q000517:prevention & control; D002034:Bumetanide / Q000494:pharmacology; D002478:Cells, Cultured; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D034622:RNA Interference; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology*; D064506:Solute Carrier Family 12, Member 2 / Q000096:biosynthesis*
chemical_list: C578878:Slc12a2 protein, mouse; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064506:Solute Carrier Family 12, Member 2; D002034:Bumetanide
keywords: Apoptosis; Erk; NKCC1; Neurons; Traumatic brain injury