An exciting study conducted by scientists at the University of California, San Francisco has revealed that an experimental drug, called ISRIB (an acronym for Integrated Stress Response inhibitor), can potentially reverse the learning and memory impairments associated with a traumatic brain injury.
Traumatic brain injury or TBI, which accounts for 30% of all brain injury, results in brain dysfunction due to bump, blow, or jolt to the brain. Most of the sport-related TBI results from concussion – one type of brain injury that shakes the brain inside the skull.
In the United States, about 21% of all TBI is associated with sports and recreational activities.
DISCOVERY OF ISRIB
ISRIB was initially discovered in 2013 in the lab of Peter Walter, professor of biochemistry and biophysics at UCSF and one of the authors of the new study. Two years later in 2015, the drug was licensed to Calico, a company conducting studies related to biology of aging and life-span.
ISRIB has shown to enhance memory formation in mice. To further check whether the drug has any effect in repairing impaired memory, Walter along with his collaborator Susanna Rosi, professor of physical therapy and rehabilitation sciences and neurological surgery at UCSF has tested the drug efficacy using two mouse models of traumatic brain injury – focal contusion and concussive brain injury.
Focal contusion is a localized brain injury that results from mechanical strike to the brain resembling a car accident. In contrast, concussive or closed brain injury causes diffuse trauma to the whole brain.
To evaluate the effect of ISRIB after focal injury, scientists used radial-arm water maze, in which mice are trained to locate an underwater hidden platform placed in one of the eight arms of the maze. While healthy mice started remembering the location only after a short training period, brain-injured mice continue to make mistakes even after a long period of training.
Three injections of ISRIB given 4 weeks after the onset of injury completely reversed the learning ability in injured mice, which became identical to their healthy counterparts. Interestingly, such improvement in memory formation continued a week after discontinuation of the drug treatment.
To check further, scientists then used a modified Barnes maze, resembling a circular platform with 40 escape holes. Of 40 escape holes, only one is connected to an escape box, allowing mice to leave the platform. This time, daily 4 injections of ISRIB given 2 weeks after the injury improved the learning and memory functions of mice as good as the normal healthy mice.
HOW ISRIB WORKS?
Any injury or stress to the cells induces a protective mechanism known as Integrated Stress Response or ISR. It acts by inhibiting protein translation, a process of synthesizing new proteins. ISRIB binds to a central component of the entire protein synthesis machinery to inhibit ISR.
As the name suggests, Integrated Stress Response Inhibitor or ISRIB improves the learning process by resuming the production of proteins necessary to strengthen neural connections and consolidate memory formation.
Using brain slices from injured mice, scientists have shown that IRS remains active for 28 days in the hippocampus, a brain region associated with memory formation. Administering ISRIB to the brain slices not only inhibits IRS but also fully restores long-term potentiation or persistent strengthening of brain connections.
According to the team, many more experiments are needed before commencing clinical trials to treat brain injured patients with ISRIB. Nevertheless, findings of this study undoubtedly bring hope to many suffering from long-lasting cognitive impairments related to traumatic brain injury.
“We need to do much more research,” Rosi said, “but I have high hopes that this drug can bring back lost memory capacity to our patients who have suffered brain injuries.”
“This is extraordinarily exciting,” said Walter, “we think that ISRIB may uncover an untapped reservoir in the brain that allows damaged memory circuits to be repaired.”
Read the original study published in PNAS.