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Britanin Ameliorates Cerebral Ischemia-Reperfusion Injury by Inducing the Nrf2 Protective Pathway
Guozhen Wu1, Lili Zhu2, Xing Yuan1
11 Department of Phytochemistry, School of Pharmacy, Second Military Medical University , Shanghai, P.R. China .
Aims:
Oxidative stress is considered the major cause of tissue injury after cerebral ischemia. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is one of the most important defensive mechanisms against oxidative stresses and has been confirmed as a target for stroke treatment. Thus, we desired to find new Nrf2 activators and test their neuronal protective activity both in vivo and in vitro.
Results:
The herb-derived compound, Britanin, is a potent inducer of the Nrf2 system. Britanin can induce the expression of protective enzymes and reverse oxygen-glucose deprivation, followed by reperfusion (OGD-R)-induced neuronal injury in primary cortical neurons in vitro. Furthermore, the administration of Britanin significantly ameliorated middle cerebral artery occlusion-reperfusion (MCAO-R) insult in vivo. We report here the crystal structure of the complex of Britanin and the BTB domain of Keap1. Britanin selectively binds to a conserved cysteine residue, cysteine 151, of Keap1 and inhibits Keap1-mediated ubiquitination of Nrf2, leading to induction of the Nrf2 pathway.
Innovation:
Britanin is a potent inducer of Nrf2. The complex crystal structure of Britanin and the BTB domain of Keap1 help clarify the mechanism of Nrf2 induction. Britanin was proven to protect primary cortical neurons against OGD-R-induced injury in an Nrf2-dependant way. Additionally, Britanin had excellent cerebroprotective effect in an MCAO-R model.
Conclusion:
Our results demonstrate that the natural product Britanin with potent Nrf2-activating and neural protective activities both in vitro and in vivo could be developed into a cerebroprotective therapeutic agent. Antioxid. Redox Signal. 27, 754-768.
Insights
The natural compound Britanin activates the Nrf2 pathway, offering significant neuroprotection against oxidative stress in stroke models. This herb-derived molecule shows promise as a therapeutic agent for cerebroprotection.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Oxidative stress is a key factor in brain injury following cerebral ischemia.
- The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is crucial for cellular defense against oxidative stress and is a therapeutic target for stroke.
- Identifying novel Nrf2 activators is essential for developing new stroke treatments.
Purpose of the Study:
- To discover new activators of the Nrf2 pathway.
- To evaluate the neuroprotective potential of identified compounds both in vitro and in vivo.
- To investigate the mechanism of action of promising Nrf2 activators.
Main Methods:
- Screening of herb-derived compounds for Nrf2 induction.
- In vitro studies using primary cortical neurons subjected to oxygen-glucose deprivation and reperfusion (OGD-R).
- In vivo studies using a middle cerebral artery occlusion-reperfusion (MCAO-R) stroke model.
- Crystal structure analysis of compound-protein interactions.
Main Results:
- Britanin, a novel herb-derived compound, was identified as a potent Nrf2 pathway inducer.
- Britanin demonstrated significant neuroprotection against OGD-R-induced injury in vitro.
- Administration of Britanin ameliorated brain damage in the MCAO-R stroke model in vivo.
- Crystal structure revealed Britanin selectively binds to Keap1 at Cys151, inhibiting Nrf2 ubiquitination and activating the Nrf2 pathway.
Conclusions:
- Britanin possesses potent Nrf2-activating and neuroprotective properties.
- The findings support Britanin's potential as a therapeutic agent for cerebroprotection.
- Britanin's mechanism involves direct inhibition of Keap1, leading to Nrf2 pathway activation.
