Remimazolam ameliorates postoperative cognitive dysfunction after deep hypothermic circulatory arrest through HMGB1-TLR4-NF-κB pathway

Background: Postoperative cognitive dysfunction (POCD) is a complication of deep hypothermic circulatory arrest (DHCA). Various amounts of neurologic dysfunctions have been shown after DHCA, which has often been attributed to systemic inflammatory response syndrome and cerebral ischemia/reperfusion injury. Remimazolam is one of the commonly used anesthetic drugs with protective actions against inflammatory diseases, such as sepsis and cerebral ischemia/reperfusion injury. Here, we determined the protective effect and potential mechanism of action of remimazolam against neuronal damage after DHCA.

Methods: A rat model of DHCA was established, and a gradient dosage of remimazolam was administered during cardiopulmonary bypass (CPB). The cognitive function of rats was evaluated by Morris water maze. Hematoxylin and eosin and TUNEL staining were performed to assess hippocampus tissue injury and neuronal Apoptosis. Inflammatory cytokines concentration were analyzed by enzyme-linked immunosorbent assay. The protein expression was analyzed using automated electrophoresis western analysis and immunohistochemical analysis.

Results: The appropriate dosage of remimazolam reduced histologic injury, neuronal Apoptosis, microglia activation, and secondary inflammatory cascades, as well as the downregulation of the expression of the HMGB1-TLR4-NF-κB pathway after DHCA, improved the memory and learning abilities in DHCA rats. Further, administration of a TLR4 Antagonist TAK-242 had a similar effect to remimazolam, while the TLR4 Agonist LPS attenuated the effect of remimazolam.

Conclusions: Remimazolam could ameliorate POCD after DHCA through the HMGB1-TLR4-NF-κB signaling pathway.

Deep hypothermic circulatory arrest; HMGB1-TLR4-NF-κB pathway; POCD; Remimazolam.