U.S. study finds drug reversing memory failure caused by traumatic brain injury

SAN FRANCISCO, July 11 (Xinhua) -- University of California, San Francisco, researchers have used an experimental drug to completely reverse severe learning and memory impairments caused by traumatic brain injury (TBI) in mice.

The drug fully restored the ability to learn and remember in the brain-injured mice even when the animals were first treated as much as a month after injury.

The drug used in the research, known as ISRIB, was discovered in 2013 in the laboratory of Peter Walter, professor of biochemistry and biophysics at UCSF and co-senior author of the new study published online this week in Proceedings of the National Academy of Sciences.

ISRIB works by blocking a part of a protective cellular system known as the Integrated Stress Response, or ISR. When cells are injured or under stress from infection or a lack of nutrients, the ISR slows down translation, the process by which the genetic instructions encoded within DNA are converted into functional proteins.

By binding to a central cellular player involved in translation, ISRIB allows stressed cells to ignore the ISR, with protein translation proceeding apace.

In the research, researchers in the laboratory of co-senior author Susanna Rosi, professor of physical therapy and rehabilitation sciences and of neurological surgery at UCSF, tested whether ISRIB, which had previously been shown by Walter and colleagues to enhance memory in normal mice, could improve the ability to learn and form memories in mice with two different types of brain injury, each of which are known to degrade learning and memory in humans.

"In general, animals with these injuries never learn well again," Rosi was quoted as saying in a news release from UCSF. "So it's remarkable that ISRIB could restore the ability to form new memories even when we delayed giving the drug for four weeks after the injury. This has not been considered possible."

Localized brain injuries called focal contusions can affect spatial memory, which helps both mice and humans navigate through the world and complete necessary everyday tasks. Concussive brain injuries, which cause diffuse trauma to the whole brain, can degrade "working memory," a temporary storage system that is critical for reasoning and decision-making.

To test ISRIB's potential effects after focal injury, both normal and brain-injured mice were placed in a "radial-arm water maze," in which they had to learn the location of a platform hidden under milky water in one of eight arms of the maze.

Mice are averse to swimming, and after a brief training period normal mice improve steadily on this task, eventually finding the platform quite quickly after being placed into the maze.

But brain-injured mice continue to make errors, by swimming into incorrect arms of the maze in search of the platform, with no sign of improvement, long after training.

However, when brain-injured mice were given three injections of ISRIB beginning four weeks after injury, their performance in the maze was indistinguishable from that of normal mice, and the restoration of their ability to learn persisted for a week after the last injection.

Given ISRIB's pharmacology, Rosi noted, the persistence of its effects is intriguing, and indicates that it may induce some durable change in the brain. "ISRIB's half-life is less than a day, and when the mice demonstrated intact memory ability a week after receiving it, we know there is only the most miniscule trace of the drug left in their bodies."

To test whether ISRIB could restore working memory after concussive brain injury, members of Rosi's lab used a modified Barnes maze, which resembles a tabletop perforated with 40 holes; one of these holes leads to an escape tunnel, which normal mice efficiently learn to locate.

As with the radial-arm water maze, brain-injured mice usually perform poorly on this test, but when the mice with concussive injuries received ISRIB injections, beginning two weeks after injury, they again performed as well as their normal counterparts.