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How ISRIB Reverses Cognitive Deficits After Traumatic Brain Injury



An experimental drug nicknamed ISRIB completely eliminates learning and memory deficits in concussed mice, as previous research has shown. Howard Hughes Medical Institute's (HHMI) team of researchers, Peter Walter, and his colleagues have now provided a better insight into the mode of action of ISRIB by putting together parts of a protein involved in cellular stress

helping researchers to modify the drug, To treat traumatic brain injury and neurodegeneration in humans, says Walter, a biochemist at the University of California, San Francisco.

ISRIB, (an acronym for Integrated Stress Response Inhibitor), is an experimental drug that reverses the effects of eIF2α phosphorylation with an IC50 of 5 nM. It has also been shown to inhibit the formation of eIF2? Phosphorylation-induced stress granules (SG) inhibited. Since it is known that the eIF2 & agr; Phosphorylation is involved in memory formation, ISRIB was tested to see if it is active in vivo and was found to easily cross the blood-brain barrier with a half-life of 8 hours

  3D printed model elF2b protein

3D-printed model of the elF2b protein
Subsequent tests in 2013 revealed that ISRIB produced significant nootropic effects in mice, as measured by spatial and anxiety states Associated learning in standard water labyrinth and conditioned environment tests. Tests in 2017 showed that the experimental drug improves the ability of brain-damaged mice to learn memory memory memories and to create memories that can be reversed by traumatic brain injuries.

Traumatic brain injury

Cells respond to stressors such as viral infections, starvation and injury in the same way: by restricting the production of new proteins. This "cellular stress response" helps keep the cells alive by giving them time to recover.

"But in many cases this reaction can be maladaptive"

says Walter.

Traumatic brain injury continually shifts the cell to stress – and the resulting decline in protein production can slow down critical cognitive processes. For example, learning and storing memories requires that brain cells produce proteins that help create lasting connections in the brain.

In 2013, after screening more than 100,000 molecules for drugs that alter the stress response, Walter and colleagues identified 28 potential candidates, including ISRIB. The team found that ISRIB maintains an important protein production line in stressed cells

But ISRIB did not dissolve well in aqueous solutions, so researchers initially did not consider it a viable drug. Close inspection revealed that ISRIB was 1000 times more potent than many of the other molecular options.

So, even the tiny amount of ISRIB that can penetrate into cells was enough to cause a reaction.

eIF2B and ISRIB

stress cells that were dosed with the drug again began to synthesize proteins – and remarkably improved ISRIB in mouse learning and memory. Last year, researchers discovered that ISRIB also restores long-term memory in concussed mice.

The team knew from previous experiments that ISRIB prevents the cellular stress response by stabilizing a protein called eIF2B, which typically boosts protein production.

In stressed cells, eIF2B blocks the activation of another protein complex that initiates protein synthesis. However, when stressed cells receive ISRIB, eIF2B remains active and cells continue to produce proteins.

To better understand how ISRIB activates and stabilizes eIF2B, Walter and his colleagues wanted to see exactly how the molecule and protein interact.

Together with Adam Frost, structural biologist and HHMI lecturer at UCSF, researchers used cryo-electron microscopy to obtain a detailed structure of ISRIB bound to eight eIF2B components.

At near-atomic resolution, where the drug binds to the protein, "Walter says." It's really amazing to see a small molecule under the microscope. "

The researchers saw that the propeller-shaped ISRIB was deep inside of eIF2B and acts as a molecular staple connecting two identical subcomplexes

is that ISRIB, which holds the eIF2B complex together, can be enough to stabilize the protein and increase its activity "

says Walter.

UCSF licensed ISRIB to Calico, a company founded by Alphabet, Google's parent company, to research aging. Knowing how ISRIB and its protein target work together could help researchers tailor the molecule to clinical trials for neurodegeneration and craniocerebral trauma.

So far, ISRIB does not seem to be toxic, maybe because it works only in stress cells, and not in cells that function normally, says Walter.

Jordan C. Tsai, Lakshmi E. Miller-Vedam, Aditya A. Anand, Priyadarshini Jaishankar, Henry C. Nguyen, Adam R. Renslo, Adam Frost, Peter Walter
Structure of nucleotide exchange factor eIF2B demonstrates mechanism of memory-enhancing Molecule
Science 30 Mar 2018: Vol. 359, Issue 6383, eaaq0939 DOI: 10.1126 / science.aaq0939

Alisa F. Zyryanova, Félix Weis, Alexandre Faille, Akeel Abo Alard, Ana Crespillo-Casado, Yusuke Sekine, Heather P. Harding, Felicity Allen, Leopold Parts, Christophe Fromont, Peter M. Fischer, Alan J. Warren, David Ron
ISRIB binding reveals a regulatory site in the nucleotide exchange factor eIF2B
Science 30 Mar 2018: Vol. 359, Issue 6383, pp. 1533-1536 DOI: 10.1126 / science.aar5129

Image: ISRIB, an experimental substance that strengthens the brain (propellant molecule, center), and its target protein, eIF2B. Credit: J. Tsai et al., Science 2018


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