Mechanisms of delayed ischemia/reperfusion evoked ROS generation in the hippocampal CA1 zone of adult mouse brain slices
Abstract ROS overproduction is an important contributor to delayed ischemia/reperfusion induced neuronal injury, but relevant mechanisms remain poorly understood. We used oxygen–glucose deprivation (OGD)/reperfusion in mouse hippocampal slices to investigate ROS production in the CA1 pyramidal cell...
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Nature Portfolio
2025-07-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-07070-x |
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| author | Yuliya V. Medvedeva Edward Sharman John H. Weiss |
| author_facet | Yuliya V. Medvedeva Edward Sharman John H. Weiss |
| author_sort | Yuliya V. Medvedeva |
| collection | DOAJ |
| description | Abstract ROS overproduction is an important contributor to delayed ischemia/reperfusion induced neuronal injury, but relevant mechanisms remain poorly understood. We used oxygen–glucose deprivation (OGD)/reperfusion in mouse hippocampal slices to investigate ROS production in the CA1 pyramidal cell layer during and after transient ischemia. OGD evoked a 2-stage increase in ROS production: 1st—an abrupt increase in ROS generation starting during OGD followed by a marked slowing; and 2nd—a sharp ROS burst starting ~ 40 min after reperfusion. We further found that a slight mitochondrial hyperpolarization occurs shortly after OGD termination. Consequently, we showed that administration of low dose FCCP or of FTY720 (both of which cause mild, ~ 10%, mitochondrial depolarization), markedly diminished the delayed ROS burst, suggesting that mitochondrial hyperpolarization contributes to ROS production after reperfusion. Zn2+ chelation after OGD withdrawal also substantially decreased the late surge of ROS generation—in line with our prior studies indicating a critical contribution of Zn2+ entry into mitochondria via the mitochondrial Ca2+ uniporter (MCU) to mitochondrial damage after OGD. Thus, reperfusion-induced mitochondria hyperpolarization and mitochondrial Zn2+ accumulation both contribute to mitochondrial ROS overproduction after ischemia. As these events occur after reperfusion, they may be amenable to therapeutic interventions. |
| format | Article |
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| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
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| spelling | doaj-art-50f20d4f23fb4fc382cc901b3676c7802025-08-20T03:37:22ZengNature PortfolioScientific Reports2045-23222025-07-0115111110.1038/s41598-025-07070-xMechanisms of delayed ischemia/reperfusion evoked ROS generation in the hippocampal CA1 zone of adult mouse brain slicesYuliya V. Medvedeva0Edward Sharman1John H. Weiss2Department of Neurology, University of California, IrvineDepartment of Neurology, University of California, IrvineDepartment of Neurology, University of California, IrvineAbstract ROS overproduction is an important contributor to delayed ischemia/reperfusion induced neuronal injury, but relevant mechanisms remain poorly understood. We used oxygen–glucose deprivation (OGD)/reperfusion in mouse hippocampal slices to investigate ROS production in the CA1 pyramidal cell layer during and after transient ischemia. OGD evoked a 2-stage increase in ROS production: 1st—an abrupt increase in ROS generation starting during OGD followed by a marked slowing; and 2nd—a sharp ROS burst starting ~ 40 min after reperfusion. We further found that a slight mitochondrial hyperpolarization occurs shortly after OGD termination. Consequently, we showed that administration of low dose FCCP or of FTY720 (both of which cause mild, ~ 10%, mitochondrial depolarization), markedly diminished the delayed ROS burst, suggesting that mitochondrial hyperpolarization contributes to ROS production after reperfusion. Zn2+ chelation after OGD withdrawal also substantially decreased the late surge of ROS generation—in line with our prior studies indicating a critical contribution of Zn2+ entry into mitochondria via the mitochondrial Ca2+ uniporter (MCU) to mitochondrial damage after OGD. Thus, reperfusion-induced mitochondria hyperpolarization and mitochondrial Zn2+ accumulation both contribute to mitochondrial ROS overproduction after ischemia. As these events occur after reperfusion, they may be amenable to therapeutic interventions.https://doi.org/10.1038/s41598-025-07070-xHippocampal sliceMitochondriaMitochondrial hyperpolarizationZn2+MCUOxygen glucose deprivation |
| spellingShingle | Yuliya V. Medvedeva Edward Sharman John H. Weiss Mechanisms of delayed ischemia/reperfusion evoked ROS generation in the hippocampal CA1 zone of adult mouse brain slices Scientific Reports Hippocampal slice Mitochondria Mitochondrial hyperpolarization Zn2+ MCU Oxygen glucose deprivation |
| title | Mechanisms of delayed ischemia/reperfusion evoked ROS generation in the hippocampal CA1 zone of adult mouse brain slices |
| title_full | Mechanisms of delayed ischemia/reperfusion evoked ROS generation in the hippocampal CA1 zone of adult mouse brain slices |
| title_fullStr | Mechanisms of delayed ischemia/reperfusion evoked ROS generation in the hippocampal CA1 zone of adult mouse brain slices |
| title_full_unstemmed | Mechanisms of delayed ischemia/reperfusion evoked ROS generation in the hippocampal CA1 zone of adult mouse brain slices |
| title_short | Mechanisms of delayed ischemia/reperfusion evoked ROS generation in the hippocampal CA1 zone of adult mouse brain slices |
| title_sort | mechanisms of delayed ischemia reperfusion evoked ros generation in the hippocampal ca1 zone of adult mouse brain slices |
| topic | Hippocampal slice Mitochondria Mitochondrial hyperpolarization Zn2+ MCU Oxygen glucose deprivation |
| url | https://doi.org/10.1038/s41598-025-07070-x |
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