title: Cytokine cascades induced by mechanical trauma injury alter voltage-gated sodium channel activity in intact cortical neurons.
abstract: Traumatic brain injury (TBI) triggers both immediate (primary) and long-term (secondary) tissue damages. Secondary damages can last from hours to days or even a lifetime. Secondary damages implicate several mechanisms, including influence of inflammatory mediators, mainly cytokines, on excitability of ion channels. However, studies should further explore the effects of inflammatory cytokines on voltage-gated sodium channels (VGSCs) and excitability in distal intact neurons.
  
  
  
  Mixed cultures of mouse cortical astrocytes and neurons were subjected to mechanical injury (trauma) to mimic TBI in vitro. Expression of various cytokines in these cultures were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. A trauma-conditioned medium with or without brain-derived neurotrophic factor (BDNF) was added to mouse primary cortical neurons for 6 and 24 h to mimic combined effects of multiple inflammatory cytokines on VGSCs. Spike behaviors of distal intact neurons were examined by whole-cell patch-clamp recordings.
  
  
  
  Mechanical injury in mixed cortical neuron-astrocyte cultures significantly increased expression levels of multiple cytokines, including interleukin (IL)-1β, IL-6, tumor necrosis factor-α, monocyte chemoattractant protein-1, chemokine (C-C motif) ligand-5, IL-10, and transforming growth factor-β1, at 6 and 24 h after injury. Incubation in trauma-conditioned medium increased functional VGSCs in neuronal membranes and Na+currents. Enhanced VGSCs were almost completely abolished by BDNF, and reinforcement of Na+currents was also reduced in a dose-dependent manner. BDNF (30 ng/mL) also significantly reversed reduced neuronal cell viability, which was induced by medium conditioned at 6 h. At 6 and 24 h, trauma-conditioned medium significantly increased spike frequency but not spike threshold.
  
  
  
  In TBI, the combined effect of inflammatory cytokines is directly involved in VGSC, Na+current, and excitability dysfunction in distal intact neurons. BDNF may partly exert neuroprotective effects by maintaining balance of VGSC function in distal intact neurons.
authors.affiliation: Department of Neurosurgery, Fuzhou General Hospital, Xiamen University Medical College, 156 North Road, West Second Ring, Fuzhou, 350025, Fujian, China.|Department of Neurosurgery, First Affiliated Hospital, Shantou University Medical College, 57 Changping Road, Shantou, 515041, Guangdong, China.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, 22 Xinling Road, Shantou, 515041, Guangdong, China.
authors.forename: Jiangtao
authors.initials: J
authors.lastname: Sheng
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital, Shantou University Medical College, 57 Changping Road, Shantou, 515041, Guangdong, China.
authors.forename: Jingfang
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital, Shantou University Medical College, 57 Changping Road, Shantou, 515041, Guangdong, China.
authors.forename: Guoyi
authors.initials: G
authors.lastname: Peng
authors.affiliation: Department of Neurosurgery, Fuzhou General Hospital, Xiamen University Medical College, 156 North Road, West Second Ring, Fuzhou, 350025, Fujian, China.
authors.forename: Jinfang
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Neurosurgery, Fuzhou General Hospital, Xiamen University Medical College, 156 North Road, West Second Ring, Fuzhou, 350025, Fujian, China.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, 22 Xinling Road, Shantou, 515041, Guangdong, China.
authors.forename: Xiaoxuan
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, 22 Xinling Road, Shantou, 515041, Guangdong, China. ksli2013@yeah.net.
authors.forename: Kangsheng
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Fuzhou General Hospital, Xiamen University Medical College, 156 North Road, West Second Ring, Fuzhou, 350025, Fujian, China. wshsen@xmu.edu.cn.
authors.forename: Shousen
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D061566:Voltage-Gated Sodium Channels
keywords: Brain-derived neurotrophic factor; Cytokine cascades; Inflammatory microenvironment; Mechanical brain injury; Nerve excitability; Voltage-gated sodium channel