Title : Sodium danshensu from radix and rhizoma salvia miltiorrhiza exerts neuroprotection against ischemia and reperfusion injury through the inhibition of ferroptosis mediated by the Nrf2/SLC7A11/GPX4 axis
Abstract:
Background: Ferroptosis, as iron-dependent, exerts a vital role in the pathogenesis and progression of ischemic stroke. Nuclear factor-E2-related factor 2 (Nrf2) can positively regulate the transcription of Recombinant Solute Carrier Family 7, member 11(SLC7A11) and glutathione peroxidase (GPX4) genes that combat lipid peroxidation in ferroptosis. Our preliminary studies demonstrated that Sodium Danshensu (SDSS) protect against cerebral ischemia and reperfusion injury (CIRI). However, further verification is required to determine whether the potential therapeutic mechanism of SDSS is associated with ferroptosis following ischemic stroke and if SDSS regulates the ferroptosis signaling pathway through nuclear transcription factor-Nrf2.
Purpose: This study aimed to clarify further that the mechanism of SDSS against CIRI is related to Nrf2-mediated ferroptosis.
Methods: Mice with transient middle cerebral artery occlusion (tMCAO) and HT22 cells with oxygen-glucose deprivation/reoxygenation (OGD/R) were induced to evaluate the biochemical features (ROS, GSH, MD and Fe2+ levels) of ferroptosis, the ferroptosis-related proteins (GPX4, SLC7A11 and Nrf2) expression and their mRNA levels after SDSS treatment. The binding of SDSS to Nrf2 was also detected by molecular docking and surface plasmon resonance (SPR) assay. Moreover, the neuroprotective effects of SDSS were investigated in Nrf2-deficient mice to elucidate the activation mechanism of the Nrf2/SLC7A11/GPX4 signaling pathway by SDSS.
Results: SDSS played a neuroprotective affection in mice and HT22 cells by restraining oxidative damage and ferroptosis and increasing the expression of SLC7A11 and GPX4 and nuclear Nrf2 transcription. SDSS activated Nrf2 directly to regulate the SLC7A11/GPX4 signaling pathway, which was further demonstrated in Nrf2-deficient mice.
Conclusion: The administration of SDSS can potentially mitigate brain damage caused by ischemia and reperfusion injury through the inhibition of ferroptosis, which is mediated by the Nrf2/SLC7A11/GPX4 axis. Therefore, SDSS shows promise as an effective Nrf2 activator for treating ischemic stroke.
