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Small molecule drug reverses cognitive effects of traumatic brain injury

ISRIB, an experimental small molecule drug identified at the University of California - San Francisco (UCSF), can reverse the cognitive and neuronal effects of traumatic brain injuries or concussions in mice weeks after an injury occurred, new research has found.

The study, presented in Proceedings of the National Academy of Sciences recently, found that ISRIB reverses the effects of traumatic brain injury (TBI) on areas of neurons called dendritic spines that are critical to cognition.

The researchers said that mice treated with the drug showed a sustained improvement in their working memory over time.

“Our goal was to see if ISRIB could ameliorate the neural effects of concussion,” Dr Michael Stryker,  a co-senior author of the study and professor of physiology at UCSF said in a statement. “

“We were pleased to find the drug was tremendously successful in normalising neuronal and cognitive function with lasting effects,” he added.

Traumatic brain injury is a leading cause of long-term neurological disability and impairs concentration and memory affecting patients’ quality of life and also remains the strongest environmental risk factor for dementia, and even a mild concussion significantly increases an individual’s risk, the researchers said.

Though the drug is known to block the integrated stress response effectively and showed evidence of improving cognition and behaviour in different mouse models, scientists so far have not been able to figure out how it does so.

To investigate this, UCSF graduate student Dr Elma Frias began to explore how the ISR and its inhibition affected neurons in the parietal cortex, a brain region involved in working memory.

Using advanced imaging techniques, Frias observed the effects of traumatic brain injury on dendritic spines, the tiny protrusions from dendrites, which form functional contacts with neighbouring axons of other neurons and are the primary site of excitatory communication between neurons, for multiple days.

These dendrites form, mature, and die on a regular basis in healthy nerve cells or neurons, and they aid in learning and memory processes. However, after concussions in the cortical region of the mouse brain, these dendrites produce a large number of spines, and the process continued as long as the researchers measured them.

Stating that though some people may find this unreasonable at first, as logic dictates that having more dendritic spines should be good for creating new memories, co-senior author of the study, Dr Susanna Rosi, a professor of physical therapy and neurological surgery at UCSF at the time of the study, said, “But in actuality, having all too many new spines is like being in a noisy room, when too many people are talking, you cannot hear the information you need.”

The researchers further found that these new spines last for very long, and most were removed within days, meaning they had not formed lasting functional connections.

When the mice were treated with the drug, they found that these abnormal behaviours were rapidly reversed.

By blocking the ISR, the drug could repair the neuronal structural changes caused by brain injury and restore normal rates of dendrite spine formation. These neuronal structural alterations were also associated with an improvement in performance to normal levels in a behavioural assay of working memory, which persisted for over a month after the final treatment, they noted in their paper.

“A month in a mouse is several years in a human, so to be able to reverse the effects of concussion in such a lasting way is really exciting,” said Frias.


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