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...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-07070-x |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | 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. |
|---|---|
| ISSN: | 2045-2322 |