Astragaloside IV attenuates ferroptosis after subarachnoid hemorrhage via Nrf2/HO-1 signaling pathway

Abstract

Subarachnoid hemorrhage (SAH) is a severe type of stroke featuring exceptionally high rate of morbidity and mortality due to the lack of effective management. Ferroptosis can be defined as a novel iron-dependent programmed cell death in contrast to classical apoptosis and necrosis. Astragaloside IV (AS-IV) is an active ingredient extracted from Astragalus membranaceus with established therapeutic effect on CNS diseases. However, the exact role of ferroptosis in Astragaloside IV-mediated neuroprotection after SAH is yet to be demonstrated. In the present study, the SAH model of SD male rats with endovascular perforation was used to gauge the neuroprotective effect of AS-IV on SAH-induced early brain injury (EBI) and to clarify the potential molecular mechanism. We found that the induction of SAH reduced the levels of SLC7A11 and glutathione peroxidase 4 (GPX4) in the brain, exacerbated iron accumulation, enhanced lipid reactive oxygen species (ROS) level, and stimulated neuronal ferroptosis. However, the administration of AS-IV and the ferroptosis inhibitor Ferrostatin-1 (Fer-1) enhanced the antioxidant capacity after SAH and suppressed the accumulation of lipid peroxides. Meanwhile, AS-IV triggered Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of SAH. The Nrf2 inhibitor ML385 blocked the beneficial effects of neuroprotection. These results consistently suggest that ferroptosis is profoundly implicated in facilitating EBI in SAH, and that AS-IV thwarts the process of ferroptosis in SAH by activating Nrf2/HO-1 pathway.

Overexpression of Heme oxygenase 1 enhances the neuroprotective effects of exosomes in subarachnoid hemorrhage by suppressing oxidative stress and endoplasmic reticulum stress

“…HO-1 decomposes heme directly, alleviating the damage caused by hemoglobin effectively, and prolonging neuronal protection. Previous studies have also shown that overexpression of HO-1 in cerebral cortex can remarkably reduce delayed cerebral vasospasm and improve the behavioral performance of SAH rats [43][44]. Secondly, heme decomposition products CO and biliverdin are powerful substances for anti-oxidative stress and anti-in ammation.…”

Elucidating the progress and impact of ferroptosis in hemorrhagic stroke

“…Most drug-related studies also focus on the up-regulation of GPX4 and whether it can be achieved as a criterion for determining whether a drug is effective for ferroptosis treatment ( Huang et al, 2022 ; Yuan B. et al, 2022 ). SLC7A11, as the critical target regulating GSH synthesis, was also found to be impaired in SAH models ( Liu et al, 2022 ). But in terms of protein expression, the reduction is not as significant as GPX4.…”

The cell‐specific roles of Nrf2 in acute and chronic phases of ischemic stroke

“…Ferroptosis is implicated in many neurological disorders such as traumatic brain injury (TBI) and in chronic neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. 54 , 55 In the field of ischemic stroke, ferroptosis is more extensively studied in hemorrhagic stroke 56 , 57 , 58 , 59 as heme and iron are blood components. Indeed, ferroptosis was observed in neonatal rat hypoxic–ischemic brain injury models.…”