An increase in voltage‐gated sodium channel current elicits microglial activation followed inflammatory responses in vitro and in vivo after spinal cord injury

Abstract

Inflammation induced by microglial activation plays a pivotal role in progressive degeneration after traumatic spinal cord injury (SCI). Voltage-gated sodium channels (VGSCs) are also implicated in microglial activation following injury. However, direct evidence that VGSCs are involved in microglial activation after injury has not been demonstrated yet. Here, we show that the increase in VGSC inward current elicited microglial activation followed inflammatory responses, leading to cell death after injury in vitro and in vivo. Isoforms of sodium channel, Nav 1.1, Nav 1.2, and Nav 1.6 were expressed in primary microglia, and the inward current of VGSC was increased by LPS treatment, which was blocked by a sodium channel blocker, tetrodotoxin (TTX). TTX inhibited LPS-induced NF-κB activation, expression of TNF-α, IL-1β and inducible nitric oxide synthase, and NO production. LPS-induced p38MAPK activation followed pro-nerve growth factor (proNGF) production was inhibited by TTX, whereas LPS-induced JNK activation was not. TTX also inhibited caspase-3 activation and cell death of primary cortical neurons in neuron/microglia co-cultures by inhibiting LPS-induced microglia activation. Furthermore, TTX attenuated caspase-3 activation and oligodendrocyte cell death at 5 d after SCI by inhibiting microglia activation and p38MAPK activation followed proNGF production, which is known to mediate oligodendrocyte cell death. Our study thus suggests that the increase in inward current of VGSC appears to be an early event required for microglia activation after injury.

Curcumin improves neural function after spinal cord injury by the joint inhibition of the intracellular and extracellular components of glial scar

“…Proinflammatory cytokines such as TNF-a and IL-1b rapidly activate astrocytes to express a large amount of IF proteins such as GFAP and cause cell body swelling, hypertrophy, and form compact scar tissue [26]. The NF-kb signaling pathway is an important pathway by which TNF-a and IL-1b play their roles [27]. TGF-b 1 and TGF-b 2 can promote glial cells to secrete extracellular inhibitory CSPG [28].…”

Riluzole promotes neurological function recovery and inhibits damage extension in rats following spinal cord injury: a meta‐analysis and systematic review

“…; Jung et al . ). Interestingly, riluzole was reported to significantly decrease the secretion of pro‐inflammatory cytokines and the expression of M1 polarization markers on microglia (Noda et al .…”

“…In contrast, an excessive influx of sodium or glutamate release can induce cell toxicity (Jung et al . ; Liu et al . ).…”

“…The inhibition of specific sodium channels has been reported to reduce inflammation and astrogliosis responses in SCI (Jung et al . ; Pappalardo et al . ).…”

“…For instance, excessive sodium influx following CNS injury can trigger the extracellular release of glutamate in presynaptic neurons, with resulting excitatory neurotoxicity to postsynaptic neurons (Nagoshi et al 2015). The inhibition of specific sodium channels has been reported to reduce inflammation and astrogliosis responses in SCI (Jung et al 2013;Pappalardo et al 2014).…”