Cytokine cascades induced by mechanical trauma injury alter voltage-gated sodium channel activity in intact cortical neurons

Background: 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. methods: 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. results: 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. conclusions: 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. © 2017 the author(s).