Esketamine accelerates emergence from isoflurane general anaesthesia by activating the paraventricular thalamus glutamatergic neurones in mice.

BACKGROUND: Delayed emergence from general anaesthesia poses a significant perioperative safety hazard. Subanaesthetic doses of ketamine not only deepen anaesthesia but also accelerate recovery from isoflurane anaesthesia; however, the mechanisms underlying this phenomenon remain elusive. Esketamine exhibits a more potent receptor affinity and fewer adverse effects than ketamine and exhibits shorter recovery times after brief periods of anaesthesia. As the paraventricular thalamus (PVT) plays a pivotal role in regulating wakefulness, we studied its role in the emergence process during combined esketamine and isoflurane anaesthesia. METHODS: The righting reflex and cortical electroencephalography were used as measures of consciousness in mice during isoflurane anaesthesia with coadministration of esketamine. The expression of c-Fos was used to determine neuronal activity changes in PVT neurones after esketamine administration. The effect of esketamine combined with isoflurane anaesthesia on PVT glutamatergic (PVTGlu) neuronal activity was monitored by fibre photometry, and chemogenetic technology was used to manipulate PVTGlu neuronal activity. RESULTS: A low dose of esketamine (5 mg kg-1) accelerated emergence from isoflurane general anaesthesia (474 [30] s vs 544 [39] s, P=0.001). Esketamine (5 mg kg-1) increased PVT c-Fos expression (508 [198] vs 258 [87], P=0.009) and enhanced the population activity of PVTGlu neurones (0.03 [1.7]% vs 6.9 [3.4]%, P=0.002) during isoflurane anaesthesia (1.9 [5.7]% vs -5.1 [5.3]%, P=0.016) and emergence (6.1 [6.2]% vs -1.1 [5.0]%, P=0.022). Chemogenetic suppression of PVTGlu neurones abolished the arousal-promoting effects of esketamine (459 [33] s vs 596 [33] s, P<0.001). CONCLUSIONS: Our results suggest that esketamine promotes recovery from isoflurane anaesthesia by activating PVTGlu neurones. This mechanism could explain the rapid arousability exhibited upon treatment with a low dose of esketamine.

Probiotic Saccharomyces boulardii attenuates cardiopulmonary bypass-induced acute lung injury by inhibiting ferroptosis.

OBJECTIVE: Acute lung injury (ALI) is one of the most common and fatal complications of cardiopulmonary bypass (CPB). Probiotics treatment has been shown to reduce lung injury in different experimental models. However, the effect of probiotics on CPB-induced ALI is still poorly understood. This study aimed to investigate whether probiotic Saccharomyces boulardii CNCM I-745 treatment protects against lung injury in a rat model of CPB. METHODS: Rats were orally gavaged with Saccharomyces boulardii CNCM I-745 once a day for 5 days before being subjected to CPB. Rats were euthanized post-CPB, and samples of lung tissue were processed for later investigation. The levels of inflammatory cytokines were measured by ELISA. The expression levels of ferroptosis markers in lungs were assessed by western blot. The microbes in feces and proximal colon of rats were analyzed by using 16S rDNA amplicon sequencing method. The ratio and maturity of conventional dendritic cells (cDCs) were determined by flow-cytometry. RESULTS: Saccharomyces boulardii CNCM I-745 treatment improved lung function, attenuated pathologic lung changes and decelerated the exacerbation of inflammatory cytokine level after experimental CPB. Saccharomyces boulardii CNCM I-745 treatment also inhibited CPB-induced ferroptosis, as evidenced by the changes of main markers of ferroptosis, namely, the increase of Glutathione peroxidase 4 (GPX4) and the decrease of Acyl-CoA synthetase long chain family member 4 (ACSL4). In addition, after Saccharomyces boulardii CNCM I-745 treatment, the ratio and maturity of conventional dendritic cells (cDCs) in the guts of rats with CPB were significantly up-regulated. CONCLUSION: Our findings suggest that probiotic Saccharomyces boulardii CNCM I-745 reduces CPB-induced lung injury through suppression of the ferroptosis in lung and up-regulation of the ratio and maturity of cDCs in gut.