Objective: Microglial activation is an essential pathological mechanism of spinal cord ischemia-reperfusion injury (SCIRI). Previous studies showed dexmedetomidine (DEX) could alleviate SCIRI while the mechanism was not clear. This study aims to investigate the role of DEX in microglial activation and clarify the underlying mechanism.
Methods: The motion function of mice was quantified using the Basso Mouse Scale for Locomotion. The expression of long non-coding RNA (lncRNA) small nucleolar RNA host gene 14 (SNHG14) was determined by qRT-PCR. The expression of high-mobility group box 1 (HMGB1) was measured by western blot. The activation of microglia was evaluated by the expression of ED-1 and the levels of TNF-α and IL-6. The interplay between SNHG14 and HMGB1 was confirmed with RNA pull-down and RIP assay. The stability of HMGB1 was measured by ubiquitination assay and cycloheximide-chase assay.
Results: DEX inhibited microglial activation and down-regulated SNHG14 expression in SCIRI mice and oxygen and glucose deprivation/reoxygenation (OGD/R)-treated primary microglia. Functionally, SNHG14 overexpression reversed the inhibitory effect of DEX on OGD/R-induced microglial activation. Further investigation confirmed that SNHG14 bound to HMGB1, positively regulated HMGB1 expression by enhancing its stability. In addition, the silence of HMGB1 eliminated the pro-activation impact of SNHG14 overexpression on DEX-treated microglia under the OGD/R condition. Finally, in vivo experiments showed SNHG14 overexpression abrogated the therapeutic effect of DEX on SCIRI mice by up-regulating HMGB1.
Conclusion: DEX accelerated HMGB1 degradation via down-regulating SNHG14, thus inhibiting microglial activation in SCIRI mice.
Keywords: Dexmedetomidine; HMGB1; lncRNA SNHG14; microglial activation; spinal cord ischemia-reperfusion injury.