Celastrol targeting Nedd4 reduces Nrf2-mediated oxidative stress in astrocytes after ischemic stroke

Journal of Pharmaceutical Analysis

Available online 7 January 2023

Journal of Pharmaceutical AnalysisAuthor links open overlay panelHighlights•

Celastrol attenuates oxidative stress after CIRI by upregulating Nrf2 in astrocytes.

Celastrol suppresses ROS generation and reduces astrocytes activation and neuron damage.

Celastrol directly binds to Nedd4 and thus inhibits Nrf2 degradation in astrocytes.

Nedd4 is a novel E3 ligase of Nrf2 and mediated K48-linked ubiquitination of Nrf2.

Abstract

Stroke is the second leading cause of death worldwide, and oxidative stress plays a crucial role. Celastrol exhibits strong antioxidant properties in several diseases; however, whether it can affect oxidation in cerebral ischemic-reperfusion injury (CIRI) remains unclear. This study aimed to determine whether celastrol could reduce oxidative damage during CIRI and to elucidate the underlying mechanisms. Here, we found that celastrol attenuates oxidative injury in CIRI by upregulating nuclear factor E2-related factor 2 (Nrf2). Using alkynyl-tagged celastrol (cel-probe) and liquid chromatography-tandem mass spectrometry, we showed that celastrol directly binds to neuronally expressed developmentally downregulated 4 (Nedd4) and then releases Nrf2 from Nedd4 in astrocytes. Nedd4 promotes the degradation of Nrf2 through K48-linked ubiquitination and thus contributes to astrocytic ROS production in CIRI, which is significantly blocked by celastrol. Furthermore, by inhibiting oxidative stress and astrocyte activation, celastrol effectively rescued neurons from axon damage and apoptosis. Our study uncovered Nedd4 as a direct target of celastrol, and that celastrol exerts antioxidative effect in astrocytes by inhibiting the interaction between Nedd4 and Nrf2 and reducing Nrf2 degradation in CIRI.

Keywords

celastrol

cerebral ischemia

reperfusion injury

oxidative stress

Nedd4

Nrf2

ubiquitylation

© 2023 The Author(s). Published by Elsevier B.V. on behalf of Xi’an Jiaotong University.

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