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Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke.

Cell (2019-05-06)
Ishraq Alim, Joseph T Caulfield, Yingxin Chen, Vivek Swarup, Daniel H Geschwind, Elena Ivanova, Javier Seravalli, Youxi Ai, Lauren H Sansing, Emma J Ste Marie, Robert J Hondal, Sushmita Mukherjee, John W Cave, Botir T Sagdullaev, Saravanan S Karuppagounder, Rajiv R Ratan
ABSTRACT

Ferroptosis, a non-apoptotic form of programmed cell death, is triggered by oxidative stress in cancer, heat stress in plants, and hemorrhagic stroke. A homeostatic transcriptional response to ferroptotic stimuli is unknown. We show that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant glutathione peroxidase 4 (GPX4). Pharmacological selenium (Se) augments GPX4 and other genes in this transcriptional program, the selenome, via coordinated activation of the transcription factors TFAP2c and Sp1 to protect neurons. Remarkably, a single dose of Se delivered into the brain drives antioxidant GPX4 expression, protects neurons, and improves behavior in a hemorrhagic stroke model. Altogether, we show that pharmacological Se supplementation effectively inhibits GPX4-dependent ferroptotic death as well as cell death induced by excitotoxicity or ER stress, which are GPX4 independent. Systemic administration of a brain-penetrant selenopeptide activates homeostatic transcription to inhibit cell death and improves function when delivered after hemorrhagic or ischemic stroke.

MATERIALS
Product Number
Brand
Product Description

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