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  2. Ulinastatin inhibited sepsis-induced spinal inflammation to alleviate peripheral neuromuscular dysfunction in an experimental rat model of neuromyopathy

Ulinastatin inhibited sepsis-induced spinal inflammation to alleviate peripheral neuromuscular dysfunction in an experimental rat model of neuromyopathy

  • J Neurochem. 2017 Oct;143(2):225-235. doi: 10.1111/jnc.14145.
Fei Xie 1 Su Min 1 Jingyuan Chen 1 Jun Yang 1 Xin Wang 1
Affiliations

Affiliation

  • 1 Department of Anesthesiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Abstract

Sepsis initiates a neuroinflammatory cascade that contributes to spinal cord inflammation and behavioral impairment, and Toll-like Receptor 4 (TLR4) is an important mediator of this cascade. In this study, we tested the hypothesis that ulinastatin (ULI) inhibits sepsis-induced spinal inflammation to alleviate peripheral neuromuscular dysfunction through the TLR4/myeloid differentiation factor 88 (MyD88)/NF-κB signaling pathway. Muscular function, spinal cord water content, and cytokine levels of spinal cord were tested in TLR4-inhibited rats subjected to cecal ligation and puncture (CLP). The normal rats were intrathecally injected with different concentrations of ULI or normal saline 60 min before CLP. At 24 h after CLP, the activation of microglia/macrophage was detected by immunofluorescence staining; and the cytokines were assayed by ELISA. The protein expression level of the TLR4 and its downstream effectors (MyD88 and NF-κB), the neuregulin-1, and the γ- and α7-nicotinic acetylcholine receptor was measured using western blotting. The protein expression of TLR4 in the spinal cord reached a maximum at 24 h post-CLP. Compared to the sham rats, the TLR4-inhibited rats showed attenuated functional impairment and cytokine release. ULI (5000 U/kg ) treatment pre-CLP significantly reduced the number of TLR4-positive microglia/macrophages as well as inflammatory mediator release in septic rats. Furthermore, the levels of TLR4, MyD88, and NF-κB and the expression level of γ-/α7-nicotinic acetylcholine receptors also decreased after ULI treatment. ULI administration may improve patient outcome by reducing the spinal inflammation through a mechanism involving the TLR4/MyD88/NF-κB signaling in sepsis.

Keywords

Toll-like receptor 4; microglia/macrophage; neuroinflammation; nicotinic acetylcholine receptor; spinal cord.

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