Hemoglobin emerges as a natural antioxidant defense in the brain

Did you know the same protein that gives blood its red color and carries oxygen throughout the body is also present inside brain cells? Hemoglobin, long celebrated for ferrying oxygen in red blood cells, has now been revealed to play an overlooked - and potentially game-changing - antioxidant role in the brain.

In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's, Alzheimer's, and aging, brain cells endure relentless damage from the aberrant (or excessive) reactive oxygen species (ROS). For decades, scientists have tried to neutralize ROS with antioxidant drugs, but most failed: they couldn't penetrate the brain effectively, unstable, or indiscriminately damaged healthy cells.

This new study, led by Director C. Justin LEE of the Center for Cognition and Sociality within the Institute for Basic Science (IBS) in Daejeon, South Korea, set out to identify the brain's own defenses against a particularly harmful form of ROS - hydrogen peroxide (H₂O₂). Using advanced imaging and molecular analysis, the team discovered that hemoglobin exists in the nucleolus of astrocytes - star-shaped brain cells critical for neuronal support - where it acts as a "pseudoperoxidase," breaking down H₂O₂ into harmless water.

The key was to uncover hemoglobin's antioxidant potential in the brain and design a 'first-in-class' compound that could selectively enhance it. By boosting a natural defense mechanism rather than introducing an external antioxidant, we achieved strong and lasting protection across multiple disease models associated with oxidative stress."

Dr. Won Woojin, first author 

The team developed KDS12025, a small, water-soluble molecule capable of crossing the blood–brain barrier. KDS12025 binds to hemoglobin's heme center and boosts its ability to decompose H₂O₂ by nearly 100-fold, without disrupting its normal oxygen-carrying function. In disease-like conditions in astrocytes, KDS12025 sharply reduced harmful H₂O₂ levels. In mouse models, oral administration through drinking water protected neurons, calmed reactive astrocytes, and restored brain function.

In animal models, oral administration through drinking water suppressed neuronal death, normalized reactive astrocytes, and restored brain function. ALS model mice showed a delayed disease onset and lived more than four weeks longer than untreated controls. In Parkinson's models, KDS12025 restored motor function, while in Alzheimer's models, it recovered memory performance. In aging mice, the treatment extended median lifespan from the typical two years to as long as three years. The drug also alleviated inflammation and joint damage in a rheumatoid arthritis model.

The study also uncovered a damaging feedback loop: excess H₂O₂ depletes astrocytic hemoglobin, weakening the brain's natural antioxidant defenses and accelerating degeneration. By boosting hemoglobin's levels and activity, KDS12025 reversed this trend, reducing oxidative stress, preserving neurons, and maintaining healthy brain function.

No previous treatment has targeted astrocytic hemoglobin as an antioxidant system, nor demonstrated such broad protective effects.

"This is a major step forward in the fight against neurodegenerative diseases. By enhancing the brain's own hemoglobin to combat oxidative stress, we are opening an entirely new therapeutic avenue," said Director Lee.

The team now plans to further study the distinct roles of α- and β-globin in the brain, refine KDS12025 derivatives for potential human use, and explore its applications in other oxidative stress–driven disorders.

This work transforms hemoglobin from a familiar oxygen transporter into a precision antioxidant defense system for the brain. It marks a potential paradigm shift in how scientists approach neurodegenerative diseases, age-related decline, and autoimmune conditions.