Abstract
Surgical brain injury (SBI) triggers microglia to release numerous inflammatory factors, leading to brain edema and neurological dysfunction. Reducing neuroinflammation and protecting the blood-brain barrier (BBB) are key factors to improve the neurological function and prognosis after SBI. Na+-K+-Cl– cotransporter 1 (NKCC1) and nuclear factor κB (NF-κB) have been implicated in the secretion of inflammatory cytokines by microglia in brain injury. This study aimed to establish the role of NKCC1 in inducing inflammation in SBI, as well as to determine whether NKCC1 controls the release of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) via phosphorylation of NF-κB in microglia, thus affecting BBB permeability and neuronal cell apoptosis. Male Sprague-Dawley (SD) rats were used to establish an SBI model. This study revealed that compared with the sham group, the expression levels of p-NKCC1, p-p65-NF-κB, and related inflammatory factor proteins in SBI model group significantly increased. After p-NKCC1 was inhibited, p-p65-NF-κB, IL-6, IL-1β, and TNF-α were downregulated, and nerve cell apoptosis and BBB permeability were significantly reduced. These findings suggest that the SBI-induced increase in p-NKCC1 exacerbates neuroinflammation, brain edema, and nerve function injury, which may be mediated by regulating the activity of p65-NF-κB that in turn influences the release of inflammatory factors.
Highlights
Brain surgery plays a major role in studying the etiology and treatment of brain diseases (Hamard et al, 2016)
The aim of this study was to investigate the relationship between Na+-K+-Cl− cotransporter 1 (NKCC1) and microglia cell-induced release of inflammatory factors after surgical brain injury (SBI), as the inhibition of NKCC1 can reduce p-p65-nuclear factor κB (NF-κB) activation, decrease the release of inflammatory factors, thereby reducing brain edema and nerve cell apoptosis as well as improving nerve function, indicating that it plays a role in brain protection
The analysis showed that the number of p-NKCC1positive astrocytes (Figures 2C,D), neurons (Figures 2E,F), and microglia (Figures 2G,H), were higher at 48 h in the SBI group relative to the sham group
Summary
Brain surgery plays a major role in studying the etiology and treatment of brain diseases (Hamard et al, 2016). After brain injury caused by various reasons, immune cells are activated, triggering the release of pro-inflammatory cytokines, resulting in the formation of an inflammatory environment in the brain, which is a feature of many brain pathologies. Neuroinflammation is a major adverse reaction that occurs after brain injury that may lead to brain edema, nerve cell apoptosis, as well as aggravated nerve function injury (Xiao et al, 2018). Microglia are stimulated to activate the nuclear factor κB (NFκB) signaling pathway, which induces cells to contribute to the generation of an inflammatory response and triggers microglia to secrete a various inflammatory factors, including interleukin1β (IL-1β), interleukin-6 (IL-6), as well as tumor necrosis factor alpha (TNF-α), which cause cellular neurotoxicity and lead to secondary brain injury (Wu et al, 2017b; Zhang et al, 2020a)
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