08 January 2020 : Animal Research
Dexmedetomidine Post-Conditioning Alleviates Cerebral Ischemia-Reperfusion Injury in Rats by Inhibiting High Mobility Group Protein B1 Group (HMGB1)/Toll-Like Receptor 4 (TLR4)/Nuclear Factor kappa B (NF-κB) Signaling Pathway
Yongyi Zhai1ADE, Yulin Zhu2BCF, Jingying Liu3EF, Kun Xie4DEF, Jingui Yu5BCD, Lingzhi Yu6BF, Hongyan Deng7AFG*DOI: 10.12659/MSM.918617
Med Sci Monit 2020; 26:e918617
Abstract
BACKGROUND: Cerebral ischemia-reperfusion injury is a pivotal cause of deaths due to cerebrovascular accident. Increased research efforts are needed to reveal the mechanism underlying its aggravation or alleviation. In this study, the effects of dexmedetomidine post-conditioning on the HMGB1/TLR4/NF-κB signaling pathway in cerebral ischemia-reperfusion rats was explored.
MATERIAL AND METHODS: Ninety rats were randomly divided into 5 groups – a sham group (Sham), a model group (I/R), a dexmedetomidine post-conditioning group (Dex), a recombinant high mobility group protein B1 group (rHMGB1), and a recombinant HMGB1+dexmedetomidine post-conditioning group (rHMGB1+Dex) – with 18 rats in each group. Longa grading, wet-dry weighing, TTC staining, HE staining, and immunohistochemical staining were used to assess brain damage. ELISA, RT-PCR, and Western blot analyses were performed to assess expression of IL-1β, TNF-α, IL-6, IL-8, HMGB1, TLR4, and NF-κB.
RESULTS: Compared with the I/R group, the neurological function score, brain water content, infarction area, and the number of COX-2- and IBA-1-positive cells in the Dex group were significantly lower, accompanied by downregulated expression of the HMGB1/TLR4/NF-κB pathway, alleviated inflammation, and oxidative stress injury in brain tissue. These trends were mostly reversed in the rHMGB1 group and rHMGB1+Dex group, but not in the Dex group. Furthermore, when compared to the Dex group, there were significant increases of H₂O₂, MDA, NO, IL-1β, TNF-α, IL-6, IL-8, HMGB1, TLR4, and p-P65 in the rHMGB1 group and rHMGB1+Dex group, in which a significant decrease of T-AOC, SOD, and p-IκBα was also detected.
CONCLUSIONS: Dexmedetomidine post-conditioning can alleviate cerebral ischemia-reperfusion injury in rats by inhibiting the HMGB1/TLR4/NF-κB signaling pathway.
Keywords: Dexmedetomidine, HMGB1 Protein, Toll-Like Receptor 4, Brain Ischemia, NF-KappaB Inhibitor alpha
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