Today we will talk about the impact of a new experimental molecule on the brain and cognitive functions. Scientists working at UC San Francisco tried a new drug on mice. Age-related brain cognitive decline began to decline in mice that received several doses of this drug, called ISRIB. In fact, some of the effects of this drug were already known. Evidence exists in the literature that this drug strengthens memory months after traumatic brain injury. It is effective in strengthening brain functions in Down syndrome. Some positive results were also obtained in tests conducted in healthy animals.
According to the report, published on December 1, 2020, when aged mice receive ISRIB, a rapid regeneration process begins in the brain and immune cells. As cells continue to regenerate, there are also noticeable changes in the cognitive function of mice. It is the first time that age-related cognitive disorders are eliminated so quickly with ISRIB acting excessively quickly. Perhaps thanks to this drug, the problems that come with aging can be regressed without becoming permanent.
ISRIB inhibits cellular stress
Prof. Dr. Peter Walter notes that their result is very important. Thanks to these data, we can conclude that cognitive dysfunction is not permanent. But with old age, we need to accept that the brain is worn out and can never be as agile as it was when we were young. This molecule may be a cure for the problems that come with aging, but it should not be expected to create miracles.
ISRIB was synthesized in 2013 by Peter Walker’s team. Walter is a respected scientist who has signed numerous important articles. He’s been studying cellular stress for years. With ISRIB, the team aims to stop cellular aging and accelerate cell regeneration. After entering the cell, ISRIB strengthens the cell’s protein production mechanism. This is not actually forcing the cell to work harder, but rather making it work more comfortably. Each cell has a quality control mechanism called integrated stress response (ISR). This mechanism comes into play when the cell is stressed. ISRIB (ISR inhibitor) stops this quality control mechanism.
Chronic Stress Disrupts Cognitive Functions
ISR’s mission is to alert the cell to dangers and unexpected problems. For example, it immediately alarms when there is an infection or other condition that will disturb the cell. He sends a message to all the workers in the factory: “stop, stop working, something is wrong.” In this way, it can interrupt the cell’s protein production line. In fact, it is very critical for a cell to function in a healthy way. When the cell is occupied by a pathogen, the most important thing should be to repel that pathogen and attract immune cells to the environment. Especially in a very vital organ such as the brain, the health of cells is very important. But everything comes at a price. High security measures can also prevent healthy cells from functioning.
In research conducted by Walter and his team, continuous activation of ISR in cells disrupts cognitive function. Chronic stress response seriously undermines the healing process, especially in people with traumatic brain injuries. In research conducted in mice, after ISRIB treatment, the ISR mechanism is shut down and restarted for a while. It’s like turning the computer off and on. When you keep your computer open for days, a slowdown occurs due to the accumulation of background programs. In the same way, too long-term stress response damages the cell. A reboot triggered by ISRIB takes effect in a few days.
Age-related cognitive impairments can be treated with ISRIB
Postdoctoral researcher Karen Krukowski, who was on the research team, subjected the animals to the water maze test, where they would practice ISRIB. In this test, mice find a platform to avoid drowning in a tank full of water. It is measured when mice learn where the platform is and how quickly they will remember it on their next attempt. Older mice take longer to learn the location of the platform and find it in subsequent repetitions compared to younger ones. But older mice that received ISRIB at the end of the three-day training performed better than their peers in the control group. They even scored as well as young mice.
In the next process, it was investigated how long the effect of ISRIB lasted. How long do the cells of mice receiving ISRIB regenerate, and how long will cognitive functions remain like this? A few weeks after the first dose of ISRIB, the researchers again subjected the mice to the water maze test. Even after 3 weeks, older mice performed as well as younger ones, and there was a noticeable difference between them and the control group.
To investigate how ISRIB is effective in the brain, scientists focused on the central hippocampus of memory. Just like a post office, the hippocampus takes all the information from outside and organizes it in order of importance and records it. It is one of the most important brain regions in the decline of age-related cognitive functions. The hippocampus is one of the first regions to be disrupted in conditions such as Alzheimer’s disease and dementia. From the first dose of ISRIB, traces of neuronal aging begin to disappear. The electrical activity of neurons is stronger, and cells respond more effectively to external stimuli. Over time, the chemical interaction of neurons, which are cells around them, becomes stronger and they make more stable connections. Especially in cells at the center of memory, such as the hippocampus, the communication of neurons among themselves is crucial for longer-term recording of information.
The effect of ISRIB on cellular aging can be transferred to clinical trials with the help of future research. Chronic activation of ISR plays a central role in numerous neurodegenerative diseases and age-related cognitive decline. Triggering and accelerating cellular aging with short-term inhibition of ISR can be therapeutic for many ailments. Researchers note that this molecule is promising in a large number of conditions, such as dementia, multiple sclerosis, Parkinson’s disease, Down syndrome.