A small molecule drug modifies the neural effects of concussion

A new study shows that a small molecule called ISRIB, which was identified at the University of California, San Francisco, can reverse the neuronal and cognitive effects of concussion in mice weeks after the injury.

ISRIB blocks the integrated stress response (ISR), a quality control process for the production of a protein that can become destructive to cells when chronically activated.

Research published on October 10, 2022 in Proceedings of the National Academy of Sciencesfound that ISRIB modifies the effects of traumatic traumatic brain injury (TBI) on areas of neurons named dendritic spines which are crucial to cognition. Mice receiving the drug also showed sustained improvements in working memory.

“Our goal was to see if ISRIB could reduce the neural consequences of concussion,” said Michael Stryker, Ph.D., co-senior author of the study and professor of physiology at UCSF. “We were pleased to find that the drug was remarkably successful in normalizing neuronal and cognitive function with long-lasting effects.”

TBI is a major cause of long-term neurological disability with impairments in concentration and memory affecting patients’ quality of life. It is also the strongest environmental risk factor for dementia – even a mild concussion significantly increases a person’s risk.

Eliminating the consequences of a concussion

ISRIB was developed in the lab of one of the senior authors, Peter Walter, Ph.D., who at the time of the study was a professor of biochemistry at UCSF, now emeritus and at Altos Labs. Previous studies have demonstrated that the molecule can effectively block the integrated stress response and have shown evidence of improved cognitive function and behavior in various mouse models of TBI. However, the cellular mechanisms by which ISR inhibition restored cognition remained unknown.

To investigate this, UCSF graduate student Elma Frias, Ph.D., began investigating how ISR and its inhibition affect neurons in parietal cortexan area of ​​the brain involved in working memory.

Using advanced imaging techniques, Frias observed the effects of TBI on dendritic spines, the primary site of excitatory communication between neurons, over several days.

In healthy conditions, neurons show a fairly stable rate spine formation, maturation, and elimination are the dynamics that support learning and memory. But after one mild concussion, the mouse cortical neurons showed a massive burst of newly generated spikes and continued to generate excessive spikes for as long as they were measured.

“Some may find this counterintuitive at first, thinking that more dendritic spines will be a good thing for creating new memories,” said co-senior author Suzanne Rosi, Ph.D., professor of physical therapy and neurological surgery at UCSF during research, now also at Altos Labs. “But really, having too many new spikes is like being in a noisy room—if too many people are talking, you can’t hear the information you need.”

These new spines, however, did not last very long, and most of them were removed within days, meaning that they had not formed strong functional synaptic connections.

These aberrant dynamics were rapidly reversed when mice were treated with ISRIB. By blocking the ISR, the drug was able to restore structural changes in neurons as a result of brain injury and restore normal indicators of spinal dynamics. These neuronal structural changes were also associated with an improvement in performance to normal levels in a behavioral test of working memory that persisted more than a month after the final treatment.

“A month in a mouse is a few years in a human, so being able to modify the effects of concussion in such a long-term way is really exciting,” Frias said.

Restoring the potential of the brain before treatment

The authors hypothesize that TBI causes persistent activation of the ISR, which in turn leads to persistent propagation of transient spikes that do not support memory formation. Future experiments will investigate whether ISRIB has similar effects on other cell types, brain regions, and cognitive tasks.

Activation of the ISR has been implicated in many neurological disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Therefore, the researchers believe that ISRIB may have therapeutic potential for several groups of patients.

Although there was no evidence of drug toxicity in mice, clinical trials The safety and efficacy of ISRIB in humans are currently being evaluated.

“This study reminds us that the brain is very plastic; it can be rewired and healed,” Rosie said. “By briefly inhibiting this stress pathway, we may be able to restore healthy synaptic and cognitive function in many neurological conditions.”