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Neuroprotective effect of a Keap1-Nrf2 Protein-Protein Inter-action inhibitor on cerebral Ischemia/Reperfusion injury
Zengxin Qi1, Yusheng Tong1, Hao Luo1
1Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, China; National Center for Neurological Disorders, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, China; Neurosurgical Institute of Fudan University, China; Shanghai Clinical Medical Center of Neurosurgery, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, China.
Abstract:
Oxidative stress has been confirmed to be closely related to the occurrence and development of cerebral ischemic/reperfusion (I/R). The Keap1-Nrf2 pathway is widely recognized as a defensive system to maintain cellular redox homeostasis. Targeting Keap1-Nrf2 interaction by small molecules to release Nrf2 should be a promising strategy to treat cerebral I/R injury. The piperazinyl-naphthalenesulfonamide 6 K was reported to be a Keap1-Nrf2 protein-protein interaction inhibitor, showing promising antioxidative effect. Herein, this study is to investigate whether 6 K could prevent brain from I/R injury. The related mechanism of oxidative stress was also elucidated using in vivo mice middle cerebral artery occlusion (MCAO) model and in vitro SH-SY5Y oxygen-glucose deprivation/reperfusion (OGD/R) model. The results indicated that treatment of 6 K markedly decreased infarct volume, apoptotic neurons and oxidative damage and promoted neurologic recovery in vivo. The cell model revealed that the reactive oxygen species (ROS) was decreased, and cell viability was increased. Western blots and immunofluorescence staining demonstrated that compound treatment promoted Nrf2 release and nuclear translocation. The downstream protective enzymes were significantly enhanced at both in vivo and in vitro levels. Collectively, 6 K is a promising protective agent against cerebral I/R injury through activation of Nrf2 to suppress oxidative stress.
Insights
Compound 6K effectively protects the brain from ischemic/reperfusion injury by activating the Keap1-Nrf2 pathway, reducing oxidative stress, and promoting recovery.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Oxidative stress is a key factor in cerebral ischemic/reperfusion (I/R) injury.
- The Keap1-Nrf2 pathway is crucial for maintaining cellular redox balance.
- Inhibiting Keap1-Nrf2 interaction to release Nrf2 is a potential therapeutic strategy for I/R injury.
Purpose of the Study:
- To investigate the protective effects of piperazinyl-naphthalenesulfonamide 6K against cerebral I/R injury.
- To elucidate the underlying mechanism involving oxidative stress and the Keap1-Nrf2 pathway.
Main Methods:
- Utilized in vivo mice middle cerebral artery occlusion (MCAO) model for cerebral I/R injury.
- Employed in vitro SH-SY5Y oxygen-glucose deprivation/reperfusion (OGD/R) model.
- Assessed infarct volume, neuronal apoptosis, oxidative damage, and neurological function.
- Analyzed Nrf2 translocation and downstream enzyme activity via Western blots and immunofluorescence.
Main Results:
- 6K treatment significantly reduced infarct volume, neuronal apoptosis, and oxidative damage in vivo.
- In vitro, 6K decreased reactive oxygen species (ROS) and enhanced cell viability.
- Compound 6K promoted Nrf2 release and nuclear translocation, upregulating protective enzymes.
Conclusions:
- 6K demonstrates significant neuroprotective effects against cerebral I/R injury.
- The mechanism involves the activation of the Keap1-Nrf2 pathway, leading to suppressed oxidative stress.
- 6K is a promising therapeutic agent for treating cerebral I/R injury.
