Abstract Postoperative cognitive dysfunction (POCD) is a significant concern for the elderly population worldwide. This study explored the effects of esketamine on aged mice with POCD and investigate its mechanism of action involving the TLR4/MyD88/MAPK pathway. We administrated esketamine, along with lipopolysaccharide or anisomycin, to the aged POCD mouse models. We assessed their cognitive function using the Morris water maze test. Additionally, we evaluated histopathological changes/neuronal apoptosis in the mouse hippocampal CA1 area through HE/TUNEL stainings. Furthermore, we measured IL‐1β/IL‐6/TNF‐α/TLR4/MyD88/MAPK (p‐p38/p38) levels in mouse hippocampal tissues using ELISA/RT‐qPCR/Western blotting. Lastly, we analyzed the interaction between TLR4 and MyD88 using a co‐immunoprecipitation assay. Our findings showed that esketamine effectively mitigated POCD in aged mice. This was evident from the improved cognitive performance observed in the Morris water maze test, characterized by reduced escape latency/increased number of platform crossing/a higher percentage of time spent in the target quadrant. Furthermore, esketamine exhibited a protective effect against neuronal apoptosis and reduced the levels of inflammatory factors. These findings suggest that esketamine exerts an anti‐inflammatory effect by downregulating TLR4/MyD88, thereby attenuating the inflammatory response associated with POCD. Additionally, esketamine suppressed the p38 MAPK pathway by inhibiting the TLR4/MyD88 signaling cascade. Esketamine demonstrated its efficacy in improving postoperative inflammation and cognitive impairment in aged mice by inhibiting the TLR4/MyD88 pathway. The activation of p38 MAPK signaling diminished the beneficial effects of esketamine in aged POCD mice. Collectively, the underlying mechanism of esketamine in mitigating POCD in aged mice involves the suppression of the TLR4/MyD88/p38 MAPK pathway.
Gut leakiness and subsequent bacterial translocation can contribute to sepsis and multiple organ failure following ethanol exposure and burn injury. Our laboratory has previously shown alterations in tight junction proteins following combined ethanol and burn injury, however, the mechanism by which this occurs remains largely unexplored. STAT3 has been shown to play a role in proliferation and differentiation of intestinal epithelial cells (IECs), but its role in regulation of tight junction proteins has yet to be established. Therefore, we examined the effect of alcohol and burn injury on STAT3 expression in intestinal epithelial cells. C57BL/6 mice were gavaged with ~3 g/kg ethanol. Four hours after gavage, mice were subjected to a ~12.5% total body surface area dorsal scald burn. One day following injury, IECs were isolated from small intestine and expression of STAT3, occludin, and a subset of claudins were examined. We observed significantly decreased STAT3 expression in ethanol and burn injured mice (p < .01) compared to shams by Western blot. In addition, we found significantly reduced levels of claudin‐1 (75%), claudin‐4 (86%), and occludin (67%) in IECs harvested from mice receiving ethanol and burn injury compared to shams. These findings suggest that alcohol and burn injury results in decreased STAT3 expression, which in turn, may play a role in altered tight junction protein expression following ethanol and burn injury. Supported by R01 AA015731 (MAC), R01 AA015731‐08S1 (MAC), R01 AA012034‐13 (EJK), T32 AA013527 (EJK) and the Dr. Ralph and Marian C. Falk Medical Research Trust (EJK).
'%3e%3ccircle r='20' fill='%23008'/%3e%3ccircle r='17.5' fill='%23fff'/%3e%3ccircle r='3.5' fill='%23008'/%3e%3cg id='d'%3e%3cg id='c'%3e%3cg id='b'%3e%3cg id='a' fill='%23008'%3e%3ccircle r='.875' transform='rotate(7.5 -8.75 133.5)'/%3e%3cpath d='M0 17.5.6 7 0 2l-.6 5L0 17.5z'/%3e%3c/g%3e%3cuse xlink:href='%23a' transform='rotate(15)'/%3e%3c/g%3e%3cuse xlink:href='%23b' transform='rotate(30)'/%3e%3c/g%3e%3cuse xlink:href='%23c' transform='rotate(60)'/%3e%3c/g%3e%3cuse xlink:href='%23d' transform='rotate(120)'/%3e%3cuse xlink:href='%23d' transform='rotate(-120)'/%3e%3c/g%3e%3c/svg%3e)