Characterization of Selenium Compounds for Anti-ferroptotic Activity in Neuronal Cells and After Cerebral Ischemia–Reperfusion Injury

Abstract

The emergence of ferroptosis as a cell death pathway associated with brain disorders including stroke and neurodegenerative diseases emphasizes the need to develop therapeutics able to target the brain and to protect neurons from ferroptotic death. Selenium plays an essential role in reducing lipid peroxidation generated during ferroptosis through its incorporation into the catalytic site of glutathione peroxidase 4. Here, we compared the anti-ferroptotic activity of several organic and inorganic selenium compounds: methylselenocysteine, selenocystine, selenomethionine, selenocystamine, ebselen, sodium selenite, and sodium selenate. All were effective against erastin-and RSL3-induced ferroptosis in vitro. We characterized the ability of the selenium compounds to release selenium and boost glutathione peroxidase expression and activity. Based on our results, we selected organic selenium compounds of similar characteristics and investigated their effectiveness in protecting against neuronal death in vivo using the cerebral ischemia-reperfusion injury mouse model. We found that pretreatment with methylselenocysteine or selenocystamine provided protection from ischemia-reperfusion neuronal damage in vivo. These data support the use of ferroptosis inhibitors for treatment and select selenium compounds for prevention of neuronal damage in ischemic stroke and other diseases of the brain where ferroptosis is implicated.

Bibliometric Analysis of Ferroptosis in Stroke From 2013 to 2021

“…Pharmacological selenium inhibits GPX4-dependent ferroptotic death, and selenome protects neurons and improves behavior following hemorrhagic stroke through regulating TFAP2c and Sp1 ( Alim et al, 2019 ). And pretreatment with selenium compounds, such as methylselenocysteine or selenocystamine, also protects I/R neuronal ferroptosis in vivo ( Tuo et al, 2021 ). Some natural products and traditional Chinese medicine-related content have also been confirmed to improve the prognosis of stroke by regulating ferroptosis.…”

Diphenyl Diselenide Alleviates Tert-Butyl Hydrogen Peroxide-Induced Oxidative Stress and Lipopolysaccharide-Induced Inflammation in Rat Glomerular Mesangial Cells

“…Moreover, ferroptosis promotes the development of DN by affecting the functions of renal podocytes, mesangial cells and renal tubular cells, which are closely related to the occurrence and development of DN [ 47 ]. In addition, studies have shown that the trace element selenium plays an important role in regulating ferroptosis [ 48 ]. Therefore, the improvement of DN by DPDS may be related to the regulation of ferroptosis, which was not covered in our study.…”

Crosstalk between regulated necrosis and micronutrition, bridged by reactive oxygen species

“…Se supplement was shown to promote GPX4 expression in follicular helper T cells, which alleviated the accumulation of lipid peroxides and protected cells against ferroptotic cell death (96). Se protected neurons from I/R-induced ferroptosis via boosting GPX expression and activity (97). Alim et al also observed that Se supplement increased the expression of selenoproteins, including GPX4, TXNRD1, GPX3, and selenoprotein P in neurons of intracerebral hemorrhage (ICH) mouse model (98).…”