Esketamine at a Clinical Dose Attenuates Cerebral Ischemia/Reperfusion Injury by Inhibiting AKT Signaling Pathway to Facilitate Microglia M2 Polarization and Autophagy
Ying Gao,1 Lu Li,1 Fang Zhao,1 Yi Cheng,1 Mu Jin,2 Fu-Shan Xue1,3 1Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, People’s Republi...
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Dove Medical Press
2025-01-01
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| author | Gao Y Li L Zhao F Cheng Y Jin M Xue FS |
| author_facet | Gao Y Li L Zhao F Cheng Y Jin M Xue FS |
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| description | Ying Gao,1 Lu Li,1 Fang Zhao,1 Yi Cheng,1 Mu Jin,2 Fu-Shan Xue1,3 1Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, People’s Republic of ChinaCorrespondence: Mu Jin, Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, No. 2 An-Zhen Road, Chao-Yang District, Beijing, 100029, People’s Republic of China, Tel +86-13366600987, Email jinmu0119@hotmail.com Fu-Shan Xue, Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, People’s Republic of China, Tel +86-13911177655, Fax +86-591-88217841, Email xuefushan@aliyun.com; xuefushan@mail.ccmu.edu.cnPurpose: This study aimed to assess the protective effect of a clinical dose esketamine on cerebral ischemia/reperfusion (I/R) injury and to reveal the potential mechanisms associated with microglial polarization and autophagy.Methods: Experimental cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in adult rats and simulated by oxygen-glucose deprivation (OGD) in BV-2 microglial cells. Neurological and sensorimotor function, cerebral infarct volume, histopathological changes, mitochondrial morphological changes, and apoptosis of ischemic brain tissues were assessed in the presence or absence of esketamine and the autophagy inducer rapamycin. The expression of biomarkers related to microglial M1 and M2 phenotypes in the ischemic brain tissues was determined by immunofluorescence staining and RT-qPCR, and the expression of proteins associated with autophagy and the AKT signaling pathway in the ischemic brain tissues was assayed by Western blotting.Results: Esketamine alone and esketamine combined with rapamycin alleviated neurological impairment, improved sensorimotor function, decreased cerebral infarct volume, and mitigated tissue injury in the MCAO rats. Importantly, esketamine promoted microglial phenotypic transition from M1 to M2 in both the MCAO rats and the OGD-treated BV-2 microglia, induced autophagy, and inactivated AKT signaling. Furthermore, the effects of esketamine were enhanced by addition of autophagy inducer rapamycin.Conclusion: Esketamine at a clinical dose attenuates cerebral I/R injury by inhibiting AKT signaling pathway to facilitate microglial M2 polarization and autophagy. Furthermore, esketamine combined autophagy inducer can provide an improved protection against cerebral I/R injury. Thus, this study provides new insights into the neuroprotective mechanisms of esketamine and the potential therapeutic strategies of cerebral I/R injury.Keywords: cerebral ischemia/reperfusion injury, esketamine, microglia polarization, autophagy, ischemic stroke |
| format | Article |
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| spelling | doaj-art-cd0fa7eb76884fd1b48e598763a7ffd72025-01-21T16:58:07ZengDove Medical PressDrug Design, Development and Therapy1177-88812025-01-01Volume 1936938799393Esketamine at a Clinical Dose Attenuates Cerebral Ischemia/Reperfusion Injury by Inhibiting AKT Signaling Pathway to Facilitate Microglia M2 Polarization and AutophagyGao YLi LZhao FCheng YJin MXue FSYing Gao,1 Lu Li,1 Fang Zhao,1 Yi Cheng,1 Mu Jin,2 Fu-Shan Xue1,3 1Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, People’s Republic of ChinaCorrespondence: Mu Jin, Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, No. 2 An-Zhen Road, Chao-Yang District, Beijing, 100029, People’s Republic of China, Tel +86-13366600987, Email jinmu0119@hotmail.com Fu-Shan Xue, Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, People’s Republic of China, Tel +86-13911177655, Fax +86-591-88217841, Email xuefushan@aliyun.com; xuefushan@mail.ccmu.edu.cnPurpose: This study aimed to assess the protective effect of a clinical dose esketamine on cerebral ischemia/reperfusion (I/R) injury and to reveal the potential mechanisms associated with microglial polarization and autophagy.Methods: Experimental cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in adult rats and simulated by oxygen-glucose deprivation (OGD) in BV-2 microglial cells. Neurological and sensorimotor function, cerebral infarct volume, histopathological changes, mitochondrial morphological changes, and apoptosis of ischemic brain tissues were assessed in the presence or absence of esketamine and the autophagy inducer rapamycin. The expression of biomarkers related to microglial M1 and M2 phenotypes in the ischemic brain tissues was determined by immunofluorescence staining and RT-qPCR, and the expression of proteins associated with autophagy and the AKT signaling pathway in the ischemic brain tissues was assayed by Western blotting.Results: Esketamine alone and esketamine combined with rapamycin alleviated neurological impairment, improved sensorimotor function, decreased cerebral infarct volume, and mitigated tissue injury in the MCAO rats. Importantly, esketamine promoted microglial phenotypic transition from M1 to M2 in both the MCAO rats and the OGD-treated BV-2 microglia, induced autophagy, and inactivated AKT signaling. Furthermore, the effects of esketamine were enhanced by addition of autophagy inducer rapamycin.Conclusion: Esketamine at a clinical dose attenuates cerebral I/R injury by inhibiting AKT signaling pathway to facilitate microglial M2 polarization and autophagy. Furthermore, esketamine combined autophagy inducer can provide an improved protection against cerebral I/R injury. Thus, this study provides new insights into the neuroprotective mechanisms of esketamine and the potential therapeutic strategies of cerebral I/R injury.Keywords: cerebral ischemia/reperfusion injury, esketamine, microglia polarization, autophagy, ischemic strokehttps://www.dovepress.com/esketamine-at-a-clinical-dose-attenuates-cerebral-ischemiareperfusion--peer-reviewed-fulltext-article-DDDTcerebral ischemia/reperfusion injuryesketaminemicroglia polarizationautophagyischemic stroke |
| spellingShingle | Gao Y Li L Zhao F Cheng Y Jin M Xue FS Esketamine at a Clinical Dose Attenuates Cerebral Ischemia/Reperfusion Injury by Inhibiting AKT Signaling Pathway to Facilitate Microglia M2 Polarization and Autophagy Drug Design, Development and Therapy cerebral ischemia/reperfusion injury esketamine microglia polarization autophagy ischemic stroke |
| title | Esketamine at a Clinical Dose Attenuates Cerebral Ischemia/Reperfusion Injury by Inhibiting AKT Signaling Pathway to Facilitate Microglia M2 Polarization and Autophagy |
| title_full | Esketamine at a Clinical Dose Attenuates Cerebral Ischemia/Reperfusion Injury by Inhibiting AKT Signaling Pathway to Facilitate Microglia M2 Polarization and Autophagy |
| title_fullStr | Esketamine at a Clinical Dose Attenuates Cerebral Ischemia/Reperfusion Injury by Inhibiting AKT Signaling Pathway to Facilitate Microglia M2 Polarization and Autophagy |
| title_full_unstemmed | Esketamine at a Clinical Dose Attenuates Cerebral Ischemia/Reperfusion Injury by Inhibiting AKT Signaling Pathway to Facilitate Microglia M2 Polarization and Autophagy |
| title_short | Esketamine at a Clinical Dose Attenuates Cerebral Ischemia/Reperfusion Injury by Inhibiting AKT Signaling Pathway to Facilitate Microglia M2 Polarization and Autophagy |
| title_sort | esketamine at a clinical dose attenuates cerebral ischemia reperfusion injury by inhibiting akt signaling pathway to facilitate microglia m2 polarization and autophagy |
| topic | cerebral ischemia/reperfusion injury esketamine microglia polarization autophagy ischemic stroke |
| url | https://www.dovepress.com/esketamine-at-a-clinical-dose-attenuates-cerebral-ischemiareperfusion--peer-reviewed-fulltext-article-DDDT |
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