When faced with stressful stimuli — anything from oxygen or nutrient deprivation to viral infections — cells have in-built safety mechanisms to ensure their survival. This elaborate series of biochemical events is known as the integrated stress response. Once initiated, a cell in this state shuts down its protein production machinery.
The integrated stress response is of particular interest to neuroscientists as these physiological safety switches have been found to be turned on in neural cells affected by traumatic brain injury, aging, and neurodegenerative disease. The question is — what if they could reset these safety switches, turning them back off again? Does this mean the cognitive impairment associated with these conditions is not as permanent as we once thought?
Scientists have made the exciting discovery that a recently-discovered drug is indeed capable of kickstarting neural cells in standby mode, getting their protein synthesis systems back online, and most promisingly, restoring cognitive function.
The drug, called ISRIB (integrated stress response inhibitor), is a product of studies by investigators at UCSF. Earlier experiments that involved administering ISRIB treatment to mice with traumatic brain injuries showed spectacular results: normal brain function was restored in a matter of hours.
"We've seen how ISRIB restores cognition in animals with traumatic brain injury, which in many ways is like a sped-up version of age-related cognitive decline," commented study lead Susanna Rosi, professor of Neurological Surgery at UCSF. "It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step."
In their latest study, Rosi and colleagues were interested in ISRIB’s potential to reverse cognitive impairment associated with aging. Two cohorts of mice (one aged and one young) were trained to navigate a maze — a cognitive task much easier for the younger mice to handle. When given a daily dose of ISRIB, however, the older mice were able to keep up with their youthful counterparts, outperforming other elderly mice who did not receive the medication. All this with no observable side effects.
Taking a closer look at the mechanism behind this boost of cognitive power, the investigators identified two key pathways that ISRIB improved: neurological activity in the hippocampus and reducing the activity of inflammatory immune cells in the brain. T cells are particularly susceptible to dysfunction as a result of aging, which has been linked to the brain’s elevated inflammatory state in conditions such as Alzheimer’s.
"This was very exciting to me because we know that aging has a profound and persistent effect on T cells and that these changes can affect brain function in the hippocampus," said Rosi.
"At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.”