Anticancer drug prevents depression and memory loss in stressed mice, pointing to new brain disease treatment

South Korean researchers have laid the groundwork for a new class of treatments to prevent and treat chronic stress-induced brain disease.

The Daegu Gyeongbuk Institute of Science and Technology announced Sunday that a research team led by Yu Seong-woon, a professor in the Department of Brain Sciences, has for the first time identified a paradoxical protective mechanism by which the p53 gene prevents the death of neural stem cells in the brain under chronic stress conditions.

Chronic stress is a leading cause of mental illnesses such as depression and anxiety disorders, as well as an elevated risk of neurodegenerative brain disease. In earlier research, Yu's team was the first in the world to report that chronic stress triggers "autophagic cell death" — a process in which cells destroy themselves — in hippocampal neural stem cells responsible for learning and memory. The new study identifies p53 as the critical brake controlling that death process.

The p53 gene is widely known as a classic "death gene" that suppresses tumor development by eliminating damaged cells. In adult hippocampal neural stem cells, however, the team found that p53 paradoxically acts as a survival factor — suppressing the activity of the autophagy-initiating complex and thereby preventing neural stem cell death.

When the researchers observed mice with p53 selectively removed from neural stem cells, the animals became extremely vulnerable to chronic stress: neural stem cells died rapidly, and the mice showed far more severe memory impairment along with depressive and anxious behavior. Inside neural stem cells exposed to stress hormones, LC3 — a key autophagy protein — bound to p53 and triggered its degradation. With that protective barrier gone, the cells ultimately died through excessive autophagy.

Conversely, administering low doses of RITA, an existing anticancer drug that activates p53, blocked the binding of LC3 to p53 and successfully prevented p53 degradation even under stress conditions. Mice that received the drug showed suppressed neural stem cell death in a chronic stress environment and were protected against both cognitive decline and depressive and anxious behavior. The finding was recognized as a key lead for developing new antidepressants, and patents for RITA's antidepressant efficacy have been registered in both South Korea and the United States.

Conventional antidepressants and anti-anxiety drugs have largely focused on relieving symptoms by balancing neurotransmitters. This research offers a fundamentally different approach — one that blocks the process by which stress kills brain cells at its source.

"We have demonstrated for the first time that p53, known to promote cell death, actually acts as a protective shield in hippocampal neural stem cells — keeping them alive against stress," Yu said. "A strategy targeting the inhibition of p53 degradation could enable the development of cell-protection-based treatments, unlike existing antidepressants that work through neurotransmitter regulation."

The research, supported by the Ministry of Science and ICT and the National Research Foundation of Korea, was published in the international journal Autophagy.