Could This New Drug Make Old Brains Sharp Again?

 The experimental drug was discovered mostly by chance while researchers were combing through 100,000 different molecules to see if any had beneficial effects. Tests of this drug show that a very small amount can rejuvenate dying neurons and perhaps help reinvigorate the brain’s learning processes. It’s exciting stuff. Researchers at the University of California San Francisco were trying to find ways to improve brain function when they decided to examine how to influence a process in our cells called “integrated stress response,” or ISR. Under ideal circumstances, the ISR is designed to discern if a cell is having difficulties producing the proteins it needs to keep itself healthy. If cells are found to be malfunctioning and making faulty proteins, the ISR is activated and “applies the brakes” to the cell’s activities. The process is designed to detect cells that are infected with a pathogen such as a virus or cells that are starting to become cancerous. In cases like those, taking a cell offline averts further harm. But when the ISR is chronically stuck in the “on” position and starts permanently shutting down functions in more and more healthy cells – especially in the brain – this can spell disaster. When this occurs, neurons can’t communicate with each other or form the neural networks that facilitate memory, learning and recall. And that’s where this experimental drug, called ISRIB or “integrated stress response inhibitor,” enters the picture.

Ensures a Healthy Stress Response

ISRIB stops ISR from shutting down cellular protein manufacturing processes in cells that are healthy, and as a result cells that would have been lost are up and running again. This appears to be a boon for memory health. When the California scientists gave very small amounts of ISRIB to aging animals who had trouble learning new tasks, it was almost like giving them new brains. Their learning abilities shot up and, at the same time, their immune cells started functioning more efficiently, too.¹ "The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress," according to researcher Peter Walter. "Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time." The investigation by Dr. Walter and his colleagues showed that roughly a day after getting ISRIB, the treated animals had observable improvements in the brain’s hippocampus – a part of the brain that plays a key role in learning and recall. Tests demonstrated that the typical signs of aging brain cells had diminished greatly. What’s more, the electrical activity of the neurons in this part of the brain was rejuvenated and neurons responded to stimulation more quickly. In addition, the neuronal connectivity in the brain was operating more efficiently and the stability of the connections was like those found in younger brains.

Recovery from Concussion

Three years ago, in the same lab, studies showed that ISRIB could restore normal brain function in mice following two types of TBIs (traumatic brain injuries), a surgical injury and a concussion. In both cases, the mice who received ISRIB could move through a maze or a tunnel better than the mice who did not receive the experimental drug. Even more exciting, the treatment was administered to the mice up to four weeks after their traumatic brain injury.²

Cancer-Fighting Potential

In other tests, ISRIB has displayed qualities that could be used in the fight against cancer. A study, also at the University California at San Francisco, showed that ISRIB can kill off aggressive cancer cells by causing them to over-produce proteins. It seems that in most circumstances these cancer cells rein in their protein-making capacities to keep from damaging themselves during the rapid growth typical of this disease. But ISRIB causes them to give in to their overwhelming appetite for protein manufacture and binge themselves to death.³ "We have learned that cancer cells become 'addicted' to protein synthesis to fuel their need for high-speed growth, but this dependence is also a liability: too much protein synthesis can become toxic," says researcher Davide Ruggero. "We have discovered the molecular restraints that let cancer cells keep their addiction under control and showed that if we remove these restraints they quickly burn out under the pressure of their own greed for protein." Interestingly, Dr. Ruggero’s research has not shown ISRIB to be effective against less aggressive cancer. On the bright side, it has not been shown to affect normal cells either.

Using ISRIB

Of course, all of these test results are impressive, but we’ll have to wait to see if the same benefits are found in humans. So far, tests have only been carried out in animals; however, the researchers say that ISRIB shows no sign of causing problematic side effects, and indeed they haven’t found it to have any side effects at all. Wonderful news if it holds up in us bipedal hairless naked apes. Dr. Walter and other researchers working with ISRIB caution against trying out ISRIB on your own – or on your friends or family – until its safety in people has been proven without question. But if this drug pans out, it could be a game-changer in helping people with older or injured brains restore their memories and cognitive function.

 

---

1. https://pubmed.ncbi.nlm.nih.gov/33258451/ 
2. https://www.washingtonpost.com/news/to-your-health/wp/2017/07/10/brain-damaged- mice-lost-their-memories-and-this-drug-restored-them/ 
3. https://pubmed.ncbi.nlm.nih.gov/29720449/