Mei Duan, Ning Yu, Jia Liu, Yang Zhao, Jing Zhang, Siyi Song, Shilei Wang
{"title":"Remimazolam Suppresses Oxidative Stress and Apoptosis in Cerebral Ischemia/Reperfusion Injury by Regulating AKT/GSK-3β/NRF2 Pathway.","authors":"Mei Duan, Ning Yu, Jia Liu, Yang Zhao, Jing Zhang, Siyi Song, Shilei Wang","doi":"10.2147/DDDT.S478692","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>The mechanism of remimazolam, a benzodiazepine that activates γ-aminobutyric acid a (GABAa) receptors, in cerebral ischemia/reperfusion (I/R) injury is not well understood. Therefore, we explored whether remimazolam activates protein kinase B (AKT)/glycogen synthase kinase-3β (GSK-3β)/nuclear factor erythroid 2-related factor 2 (NRF2) to attenuate brain I/R injury in transcerebral I/R-injured rats and transoxygenic glucose deprivation/reperfusion (OGD/R)-injured SY5Y cells.</p><p><strong>Material and methods: </strong>Remimazolam was added at the beginning of cell and rat reperfusion, and the PI3K/AKT inhibitor LY294002 was added to inhibit the AKT/GSK-3β/NRF2 pathway 24 h before cellular OGD/R treatment and 30 min before rat brain I/R treatment. The viability and apoptosis rate of SY5Y cells, neurological deficit score, cerebral infarction volume and morphological changes of rat brain cells as well as the protein expression of Bax, Bcl2, Caspase 3, Cleaved-Caspase 3 and the number of TdT-mediated dUTP Nick-End Labeling (TUNEL)-positive cells in the penumbral region were detected. Reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), NRF2, heme oxygenase 1 (HO-1), AKT, P-AKT, GSK-3β, P-GSK-3β protein expression, and nuclear translocation of NRF2 were measured in cell and animal assays.</p><p><strong>Results: </strong>Reduced SY5Y cell viability and increased apoptosis caused by OGD/R injury, elevated neurological deficit scores and cerebral infarct volume induced by brain I/R injury in rats, cerebral cell injury, as well as elevated Bax, Cleaved-Caspase 3, decreased Bcl2, and increased number of TUNEL-positive cells in rat brain tissue were all moderated by remimazolam. Decreased GSH-Px, SOD and Elevated MDA, ROS induced by OGD/R-injured SY5Y cells and brain I/R-injured rats were moderated by remimazolam. Meanwhile, remimazolam increased NRF2, HO-1, P-AKT, P-GSK-3β, and the nuclear accumulation of NRF2. The PI3K/AKT inhibitor LY294002 reversed the role of remimazolam in brain I/R injury.</p><p><strong>Conclusion: </strong>This study demonstrates that remimazolam activates the AKT/GSK-3β/NRF2 pathway, thereby attenuating oxidative stress and apoptosis to protect against brain I/R injury.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"111-128"},"PeriodicalIF":4.7000,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725640/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Design, Development and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/DDDT.S478692","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction: The mechanism of remimazolam, a benzodiazepine that activates γ-aminobutyric acid a (GABAa) receptors, in cerebral ischemia/reperfusion (I/R) injury is not well understood. Therefore, we explored whether remimazolam activates protein kinase B (AKT)/glycogen synthase kinase-3β (GSK-3β)/nuclear factor erythroid 2-related factor 2 (NRF2) to attenuate brain I/R injury in transcerebral I/R-injured rats and transoxygenic glucose deprivation/reperfusion (OGD/R)-injured SY5Y cells.
Material and methods: Remimazolam was added at the beginning of cell and rat reperfusion, and the PI3K/AKT inhibitor LY294002 was added to inhibit the AKT/GSK-3β/NRF2 pathway 24 h before cellular OGD/R treatment and 30 min before rat brain I/R treatment. The viability and apoptosis rate of SY5Y cells, neurological deficit score, cerebral infarction volume and morphological changes of rat brain cells as well as the protein expression of Bax, Bcl2, Caspase 3, Cleaved-Caspase 3 and the number of TdT-mediated dUTP Nick-End Labeling (TUNEL)-positive cells in the penumbral region were detected. Reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), NRF2, heme oxygenase 1 (HO-1), AKT, P-AKT, GSK-3β, P-GSK-3β protein expression, and nuclear translocation of NRF2 were measured in cell and animal assays.
Results: Reduced SY5Y cell viability and increased apoptosis caused by OGD/R injury, elevated neurological deficit scores and cerebral infarct volume induced by brain I/R injury in rats, cerebral cell injury, as well as elevated Bax, Cleaved-Caspase 3, decreased Bcl2, and increased number of TUNEL-positive cells in rat brain tissue were all moderated by remimazolam. Decreased GSH-Px, SOD and Elevated MDA, ROS induced by OGD/R-injured SY5Y cells and brain I/R-injured rats were moderated by remimazolam. Meanwhile, remimazolam increased NRF2, HO-1, P-AKT, P-GSK-3β, and the nuclear accumulation of NRF2. The PI3K/AKT inhibitor LY294002 reversed the role of remimazolam in brain I/R injury.
Conclusion: This study demonstrates that remimazolam activates the AKT/GSK-3β/NRF2 pathway, thereby attenuating oxidative stress and apoptosis to protect against brain I/R injury.
期刊介绍：
Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications.
The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas.
Specific topics covered by the journal include:
Drug target identification and validation
Phenotypic screening and target deconvolution
Biochemical analyses of drug targets and their pathways
New methods or relevant applications in molecular/drug design and computer-aided drug discovery*
Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes)
Structural or molecular biological studies elucidating molecular recognition processes
Fragment-based drug discovery
Pharmaceutical/red biotechnology
Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products**
Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development
Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing)
Preclinical development studies
Translational animal models
Mechanisms of action and signalling pathways
Toxicology
Gene therapy, cell therapy and immunotherapy
Personalized medicine and pharmacogenomics
Clinical drug evaluation
Patient safety and sustained use of medicines.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
