A new study has shed light on how an experimental drug can reverse some of the neural damage associated with traumatic brain injury. The findings lay the groundwork for a future drug that could potentially prevent the cognitive deficits that follow on from concussion.
The findings come from a team of researchers at the University of California, San Francisco investigating a signaling pathway called the integrated stress response (ISR). This is a general cellular mechanism that is triggered in the presence of environmental stresses and often leads to a shutdown in the protein production facilities within cells.
The research initially began by focusing on finding drugs that can block the ISR in the brain as a way of treating neurodegenerative diseases such as Alzheimer's and Parkinson's. One drug, dubbed ISRIB (ISR Inhibitor), has proved successful in improving cognition across several animal models of brain diseases, so the researchers set out to explore whether the drug had the same beneficial effects when treating more acute types of brain injury.
“Our goal was to see if ISRIB could ameliorate the neural effects of concussion,” explained co-senior author Michael Stryker. “We were pleased to find the drug was tremendously successful in normalizing neuronal and cognitive function with lasting effects.”
Across different mouse models of traumatic brain injury, ISRIB was seen to improve behavior and cognition. But exactly how the drug was doing this was still unclear.
This new study, published in the journal PNAS, zoomed in on a part of the brain called the parietal cortex. This region plays a role in working memory, and sophisticated imaging technology was used to highlight what happens here following brain injury.
Attention focused on how brain injury altered formation of dendritic spines, the connective pathways between neurons. Following a mild concussion, the researchers saw a flurry of new dendritic spines appear in the parietal cortex but as co-senior author Susanna Rosi explained, this is generally not a good thing.
“Some may find this counterintuitive at first, assuming more dendritic spines would be a good thing for making new memories,” said Rosi. “But in actuality, 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.”
It's hypothesized an acute brain injury can activate an ongoing integrated stress response (ISR) that subsequently leads to persistent proliferation of dendritic spines damaging a person's cognition. And in the mouse models studied, when ISRIB was administered the brain's normal spine dynamics returned, alongside improvements to cognition.
Of course, these results are only so far demonstrated in animal models so there is plenty more work to do before we get to a drug that can be quickly given to people suffering from concussion. Human safety trials are already underway testing ISRIB for toxicity and preliminary use in neurodegenerative disease.
“This study reminds us that the brain is very plastic; it can be rewired and healed,” added Rosi. “By briefly inhibiting this stress pathway, we may be able to restore healthy synaptic and cognitive function in many neurological conditions.”
The new study was published in the journal PNAS.
Source: UCSF