Abstract
Cerebral ischemic stroke (CIS) has become the second leading cause of death worldwide, which is largely related to cerebral ischemia reperfusion injury (CIRI). Surgical intervention is a reliable treatment for CIS, which predictably causes cerebral reperfusion. Therefore, the choice of anesthetic drugs has important clinical significance. Isoflurane (ISO), one of the most used anesthetics, attenuates cognitive impairment and has brain protective effects. However, the role of isoflurane in regulating autophagy and its regulatory mechanism on inflammation in CIRI are still unclear. The middle cerebral artery occlusion (MCAO) method was used to establish a rat model of CIRI. After 24 h of reperfusion, all rats were evaluated by mNSS scoring and dark avoidance experiment. Western blotting and immunofluorescence were used to examine the expression of key proteins. Compared with the sham group, the MCAO group showed increased neurobehavioral scores and decreased cognitive memory function (P < 0.05). As for the ISO-treated MCAO rats, the neurobehavioral score was significantly decreased, the expression of AMPK, ULK1, Beclin1, and LC3B was significantly increased, and the cognitive and memory functions were also significantly improved (P < 0.05). After inhibition of autophagy pathway or key protein AMPK in autophagy, neurobehavioral scores and protein expression of NLRP3, IL-1β, and IL-18 were significantly increased (P < 0.05). Isoflurane post-treatment may enhance autophagy by activating the AMPK/ULK1 signaling pathway and further inhibit the release of inflammatory factors from NLRP3 inflammasomes, thereby ameliorating neurological function and cognitive impairment and exerting a protective effect on the brain in CIRI rats.
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The datasets used and/or analyzed in during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
First of all, a very sincere thanks to Sheng Wang and Jiangwen Yin for their contributions to the study design and data analysis. Second, thanks to Nian Li, Xu Zhang, and Xinlei Qin for their efforts in the implementation of the study. Finally, thanks to Ketao Ma, Yan Li, and Ruixue Wang for their guidance on experimental methods.
Funding
This work was supported by the National Natural Science Foundation of China (82,160,235 and 81,860,249), and the Scientific Research Project of Shihezi University (ZZZC2022070).
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Sheng Wang, Jiangwen Yin, and Jingwen Zhai contributed to the study design and revised the manuscript. Jingwen Zhai, Nian Li, and Xu Zhang conducted the experiment and collected and analyzed the data. Ketao Ma, Yan Li, Ruixue Wang and Xinlei Qin provided assistance in experiment performing. Jingwen Zhai and Nian Li wrote the manuscript. All authors reviewed and approved the final manuscript.
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Zhai, J., Li, N., Zhang, X. et al. Isoflurane Enhances Autophagy by Activating AMPK/ULK1, Inhibits NLRP3, and Reduces Cognitive Impairment After Cerebral Ischemia–Reperfusion Injury in Rats. J Mol Neurosci 73, 549–562 (2023). https://doi.org/10.1007/s12031-023-02135-w
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DOI: https://doi.org/10.1007/s12031-023-02135-w