Study identifies drug that reverses “neuronal and cognitive effects” of concussion in mice
By Fadhil Hussain. This article was initially published in our Concussion Update newsletter; please consider subscribing.
A study published in the Proceedings of the National Academy of Sciences (PNAS) has identified a promising approach to treating cognitive deficits after a concussion. The study found that using a small molecule (ISRIB) to inhibit the integrated stress response (ISR) reversed long-lasting cognitive deficits after a concussion in mice. According to a press release from the University of California, the integrated stress response is “a quality control process for protein production that can disrupt the normal function of cells when it is chronically activated.” Targeting the integrated stress response could treat cognitive deficits “that develop after even mild TBI.”
The researchers at UCSF gave mice a mild closed-head concussive injury (CHI), then used advanced imaging techniques to watch how neuronal spines changed after the injury. They also measured the effect of ISR inhibition on the dynamics of these spines and working memory. According to the press release, “In healthy conditions, neurons show a fairly consistent rate of spine formation, maturation and elimination–dynamics that support learning and memory.” Throughout the days following injury, mice that received a concussion showed a significant increase in spine formation and deficits in working memory. Co-senior author Dr. Susanna Rosi, PhD, explained, “having all too many new spines is like being in a noisy room – when too many people are talking, you can’t hear the information you need.”
The mice were given a small molecule ISR inhibitor (ISRIB) once daily on days 14-18 post-injury. At day 15, only one day after the first dose, spine formation in mice in the CHI group returned to control levels and remained stable for the rest of the study. The mice also regained full working memory after ISRIB treatment. The restorative effects were maintained weeks after the drug left their system. Notably, there were no effects of ISRIB treatment on spine measurements in the control group.
The press release states, “TBI is a leading cause of long-term neurological disability, with impairments in concentration and memory affecting patients’ quality of life. It’s also the strongest environmental risk factor for dementia—even a mild concussion significantly increases an individual’s risk.” Co-senior author Dr. Michael Stryker, PhD, was “pleased to find the drug was tremendously successful in normalizing neuronal and cognitive function with lasting effects.” The research team hopes to examine whether similar observations extend to various brain regions, and clinical trials are currently testing the safety and efficacy of the drug in humans.