Dexmedetomidine alleviates hippocampal neuronal loss and cognitive decline in rats undergoing open surgery under sevoflurane anaesthesia by suppressing CCAAT/enhancer‐binding protein beta

Abstract

Dexmedetomidine (Dex) may exert neuroprotective effects by attenuating inflammatory responses. However, whether Dex specifically improves postoperative cognitive dysfunction (POCD) by inhibiting microglial inflammation through what pathway remains unclear. In this study, the POCD model was constructed by performing open surgery after 3 h of continuous inhalation of 3% sevoflurane to rats, which were intraperitoneally injected with 25 μg/kg Dex .5 h before anaesthesia. The results displayed that Dex intervention decreased rat escape latency, maintained swimming speed and increased the number of times rats crossed the platform and the time spent in the target quadrant. Furthermore, the rat neuronal injury was restored, alleviated POCD modelling‐induced rat hippocampal microglial activation and inhibited microglial M1 type polarization. Besides, we administered Dex injection and/or CCAAT/enhancer‐binding protein beta (CEBPB) knockdown on the basis of sevoflurane exposure and open surgery and found that CEBPB was knocked down, resulting in the inability of Dex to function, which confirmed CEBPB as a target for Dex treatment. To sum up, Dex improved POCD by considering CEBPB as a drug target to activate the c‐Jun N‐terminal kinase (JNK)/p‐38 signaling pathway, inhibiting microglial M1 polarization‐mediated inflammation in the central nervous system.

Anesthesia-mediated neuroinflammatory sequelae in post operative cognitive dysfunction: mechanisms and therapeutic implications

“…Cell culture and animal models of dexmedetomidine administration revealed anti-inflammatory phenotype effects (22)(23)(24)(25)243). Experiments utilizing in vitro BV-2 microglia revealed that dexmedetomidine incubation resulted in an increase in M2 polarization mediated through an increase in Akt phosphorylation (22).…”

“…Another identified mechanism of antiinflammatory microglial polarization has been through an increase in Nrf2/HO-1 signaling resulting in inhibition of NLRP3 inflammasome activation (23). When treating mice exposed to sevoflurane, 25 μg/kg dexmedetomidine administration was found to attenuate CEBPB-mediated microglial inflammatory phenotypes (24). In a similar study, mice treated with 40 ml/kg dexmedetomidine (3.3 μg/ml) prior to LPS injection resulted in a decrease in microglial activation and in oxidative stress markers when compared to 10 ml/kg of propofol (3 mg/ml) (26).…”

“…Nimodipine administration partially restored abhorrent expression of IL-6, IL-8, caspase-3, and TNF-α when administered with sevoflurane (253). α 2 -Adrenergic receptor agonism Dexmedetomidine has been shown to have neuroprotective effects in models of sevoflurane-induced cognitive decline through targeting CCAAT/enhancer binding protein beta (CEPBPB) and activating the c-Jun N-terminal kinase (JNK)/p-38 (24). Through JNK/p-38 activation, dexmedetomidine suppresses M1 microglial polarization and reverses neuronal injury in the setting of sevoflurane-exposure (24).…”