Quercetin alleviates subarachnoid hemorrhage‐induced early brain injury via inhibiting ferroptosis in the rat model

Abstract

Early brain injury (EBI) refers to a series of pathophysiological brain lesions that occur within 72 hr after subarachnoid hemorrhage (SAH), which is an extremely crucial factor in the poor prognosis of patients. In EBI, ferroptosis has been proven to cause neuronal death. Quercetin (QCT) is effective in deactivating reactive oxygen species (ROS), inhibiting lipid peroxidation, and even chelating iron, but its role in SAH remains unclear. In this study, the mortality rate, severity grade of SAH, brain water content (BWC), blood–brain barrier permeability, and neurological function of the rats were detected. Moreover, mitochondrial morphology in cortical neurons were observed and their sizes were subsequently quantified. The levels of lipid peroxidation on glutathione and malondialdehyde (MDA) and glutathione peroxidase (GSH‐Px) were determined, whereas the protein expressions of glutathione peroxidase 4 (GPX4), SLC7A11 (xCT), transferrin receptor 1 (TfR1), and ferroportin‐1 (FPN1) were analyzed by western immunoblotting. The neurodegeneration involved in EBI was investigated by fluoro‐Jade C staining, while iron staining was utilized to measure iron content. Our results showed that inhibition of ferroptosis by QCT could suppress EBI and improve neurological function in SAH rats. QCT increased the expression levels of GPX4, xCT, and FPN1, while downregulated TfR1, and exerted protective effects on neurons as well as alleviated iron accumulation and lipid peroxidation in the cortex of SAH rats. In conclusion, our study revealed that QCT might alleviate the EBI by inhibiting ferroptosis in SAH rats.

Ferroptosis in early brain injury after subarachnoid hemorrhage: review of literature

“…The results showed that the expression of GPX4 decreased and the level of lipid peroxidation increased in the brain of rats 24 h after SAH; overexpression of GPX4 could reduce lipid peroxidation, inhibit neuronal death, and then improve brain edema and neurological damage in rats [ 147 ]. In the SAH rat experiment, quercetin (QCT) downregulated TFR1 by increasing the expression of GPX4, SLC7A11 (xCT), and FPN1, thereby inhibiting neuronal ferroptosis and alleviating EBI injury [ 148 ]. Therefore, the reduction of GPX4 expression may play an important role in neuronal ferroptosis in early brain injury, while its overexpression is neuroprotective [ 147 ].…”

Pharmacological Inhibition of Ferroptosis as a Therapeutic Target for Neurodegenerative Diseases and Strokes

“…Astragaloside IV, [ 335 ] PKR inhibitor C16, [ 347 ] netrin‐1, [ 398 ] quercetin, [ 399 ] taurine, [ 400 ] puerarin, [ 345 ] an inhibitor of inducible nitrite oxide synthase L‐NIL, [ 401 ] resveratrol and selisistat, [ 348 ] cepharanthine, [ 344 ] baicalin, [ 334 ] Fer‐1, [ 333 , 402 ] and Lip‐1 [ 346 ] alleviate early brain injury after SAH through inhibiting ferroptosis ( Table 6 ).…”