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Selenium Appears Protective in Animal Model of Stroke
Why That Could Translate Into Treatment

Article In Brief

Researchers found that pharmacological selenium blocked a form of cell death in an animal model of stroke. Independent experts say the approach opens up new potential therapeutic avenues for research.

In a mouse model of hemorrhagic stroke, scientists were able to block a form of cell death, ferroptosis, and protect the brain using high pharmacological levels of selenium, a nutrient found in the human diet and in the brain.

The experimental drug also worked at reducing the events that occur after ischemic stroke, the research team reported in the May issue of Cell.

The findings offer the possibility that a similar technique might work to treat stroke in humans, said the senior author of the study, Rajiv R. Ratan, MD, PhD, the Winifred Masterson Burke professor of neurology and neuroscience and associate dean at Weill Cornell Medicine and executive director of the Burke Neurological Institute.

Scientists have identified ferroptosis as yet another trigger of cell death, he explained. Oxidative stress in cancer cells, heat stress in plants, and hemorrhagic stroke in the brain have all been linked to ferroptosis, Dr. Ratan said.

“Selenium drives a transcriptional program that regulates this kind of cell death,” he explained.

“Selenium is an essential micronutrient that is necessary for synthesizing selenocysteine, an amino acid important for cellular functioning,” Dr. Ratan said. He noted that many people are deficient in selenium—naturally and from their diets—and that adding selenium via a novel selenium-containing peptide could be a way to protect brain cells against ferroptosis in the throes of a stroke and for those with selenium deficiency, from fertility, cognitive, thyroid, and endurance problems. Brazil nuts, yellowfin tuna and other fish, and ham are good dietary sources of selenium, he said.

Study Design, Findings

To better understand the role of selenium in stroke, the research team mapped the molecular pathway following stroke in an animal model. They observed that genes in the selonome pathway are upregulated following stroke. The damaged neurons respond to the cell process by inducing selenoproteins, Dr. Ratan explained, and specifically an antioxidant called glutathione peroxidase 4 (GPX4). This antioxidant is necessary to protect against ferroptotic cell death.

At first, the investigators delivered selenium directly into the ventricle but observed there was a narrow therapeutic window. They then created a Tat-linked selenoprotein peptide (SelPep) to carry its cargo into the brain. They tested it and found that it had “a wide therapeutic window and no apparent toxicity,” said Dr. Ratan. This enabled them to use an intraperitoneal injection.

The team then infused a single pharmacological dose of a Tat-fusion protein containing a selenium peptide within two to six hours of the injury and watched as the treatment augmented GPX4 and other genes (TFAP2c and Sp1) in the transcriptional selenome program.

“There was an orchestrated activation of genes that came to the rescue of the damaged neurons,” said Dr. Ratan. “It protected the neurons from further damage and the animal's stroke-induced behaviors improved. (They used measures of spatial and sensory neglect to measure functional recovery.)

The drug also worked to reduce oxidative damage from ischemic stroke when given two hours after the injury, and this also led to functional improvements in animals.

The researchers conducted further studies to determine the protective mechanism at work. When they forced GPX4 expression two weeks before the hemorrhagic injury, they observed a dramatic reduction in cell death. Again, they believe it was due to GPX4's effects on preventing ferroptosis.

“Knowledge of how to drive GPX4 expression pharmacologically in the brain and other organs has clear therapeutic implications for hemorrhagic stroke, and possibly other CNS and non-CNS conditions associated with ferroptotic death,” the scientists wrote in the Cell paper.

“Selenium supplementation led to protection in the face of ferroptotic insults. What was unexpected,” they added, “was that Se [pharmacological selenium] supplementation could drive transcription of a host of selenoproteins.”

Selenium induced significant changes in the expression of hundreds of genes, including the mitochondrial and nuclear forms of GPX4. In other studies, the researchers showed they could induce GPX4 expression in the heart and liver, as well as the brain, suggesting its potential use in other diseases associated with ferroptosis.

“I've been studying antioxidants for 25 years,” said Dr. Ratan. “Nature is trying to tell us something,”

He and his colleagues are building more peptides to better understand the therapeutic window for a number of diseases.

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“They found that selenium, even with a single dose, protected the brain. This had significant therapeutic potential by altering transcription and inhibiting cell death induced by ferroptosis.

—DR. LOUISE D. MCCULLOUGH

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“There was an orchestrated activation of genes that came to the rescue of the damaged neurons. It protected the neurons from further damage and the animal's stroke-induced behaviors improved.”

—DR. RAJIV R. RATAN

Expert Commentary

“The whole selenium angle to manipulate ferroptosis is unique,” said Richard Keep, PhD, director of the Crosby Neurosurgical Laboratories, associate chair for research in neurosurgery, and professor of neurosurgery and neuroanatomy, and molecular and integrative physiology at Michigan Medicine. Dr. Keep studies the blood-brain barrier and also hemorrhagic stroke. He believes that ferroptosis is an important mechanism of cell death after hemorrhagic stroke, but that the field is hampered by how to specifically affect this cell death pathway.

“They unexpectedly found that their selenium treatment has effects on GPX4 transcription rather than directly affecting its activity,” Dr. Keep said. “They are trying to boost the animal's natural defense mechanisms against hemorrhagic and ischemic stroke with an extra dose of selenium, and that has advantages. This opens up a new area of investigation into these protective proteins.”

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“They are trying to boost the animal's natural defense mechanisms against hemorrhagic and ischemic stroke with an extra dose of selenium, and that has advantages. This opens up a new area of investigation into these protective proteins.”

—DR. RICHARD KEEP

“The scientists did a rigorous evaluation of genes upregulated in hemorrhagic stroke and found that neurons respond by inducing selenoproteins,” said Louise D. McCullough, MD, PhD, professor and chair of the department of neurology at McGovern Medical School at the University of Texas Health Science Center at Houston and chief of neurology at Memorial Hermann Hospital. “They found that selenium, even with a single dose, protected the brain. This had significant therapeutic potential by altering transcription and inhibiting cell death induced by ferroptosis.”

She explained that hemorrhagic stroke involves iron toxicity and there have been several clinical trials using iron chelators that have not met their primary endpoints. “Targeting cell death mechanisms and lipid damage induced by iron may be a better approach,” she added. Interestingly, “selenium was also protective in ischemic stroke models, so it could be a new therapy for that, as well.”

Disclosures

Drs. Ratan, Keep, and McCullough had no competing interests.

Link Up for More Information

•. Alim I, Caulfield JT, Chen Y, et al. Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke https://www.cell.com/cell/fulltext/S0092-8674(19)30327-7. Cell 2019; Epub 2019 May 2.
    •. Ingold I, Berndt C, Schmitt S, et al. Selenium utilization by GPX4 Is required to prevent hydroperoxide-induced ferroptosis https://www.cell.com/cell/fulltext/S0092-8674(17)31438-1. Cell 2018;172(3): 409–422.