Researchers Discover Compound That Could Revolutionize Traumatic Brain Injury Treatment

The research shows for the first time that this compound, which consists of four amino acids, can produce therapeutic effects in brain injuries on its own, without requiring the administration of any additional drugs.

An international research collaboration led by the biotechnology company Aivocode, together with scientists from the Institute for Advanced Chemistry of Catalonia (IQAC) of the Spanish National Research Council (CSIC), has identified a small molecule that shows strong protective effects in the brain after injury. The molecule, known as CAQK, is a peptide composed of four amino acids and demonstrated notable benefits in mouse models of traumatic brain injury.

In experiments involving animals (mice and pigs), CAQK was delivered intravenously soon after the injury occurred. The peptide was shown to travel specifically to damaged regions of the brain, guided by a protein that becomes highly abundant in injured tissue after trauma. Once concentrated in these areas, CAQK reduced inflammation, limited cell death, and lessened overall damage to brain tissue. In mice, treatment also led to better functional recovery, with no signs of toxicity.

The findings, reported in the journal EMBO Molecular Medicine, suggest a promising new direction for therapies aimed at injured brain tissue. The work was coordinated by Aivocode (a spin-off of the Sanford Burnham Prebys Institute) based in San Diego, California, and carried out in partnership with the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) and the University of California, Davis.

Aivocode was founded by researchers Aman P. Mann, Sazid Hussain, and Erkki Ruoslahti (authors of the study), and the company plans to apply for approval from the U.S. Food and Drug Administration (FDA) to launch Phase I clinical trials in humans. While no timeline has been announced, CAQK’s properties as a short peptide that can be produced efficiently and penetrate tissue effectively make it a compelling candidate for further drug development.

Traumatic Brain Injury

Traumatic brain injury (TBI) is brain damage typically caused by blows to the head, such as those resulting from traffic accidents, workplace incidents, or falls. It is estimated to affect around 200 people per 100,000 inhabitants each year. Currently, treatment focuses on stabilizing the patient by reducing intracranial pressure and maintaining blood flow, but there are no approved drugs to halt brain damage or its secondary effects, such as inflammation or cell death. In addition, the therapies under investigation require direct injections into the brain, an invasive technique that can cause complications.

“The current interventions for treating acute brain injury aim to stabilize the patient by reducing intracranial pressure and maintaining blood flow, but there are no approved drugs to stop the damage and secondary effects of these injuries,” explains Dr. Pablo Scodeller, researcher at IQAC-CSIC and co-author of the study.

The Great Challenge of Neurology

Finding a non-invasive way to treat an injured brain is one of the major challenges in neurology. This study moves in that direction, building on previous work carried out by the researchers in 2016 and published in Nature Communications.

At that time, researcher Aman P. Mann, together with Pablo Scodeller, working in the laboratory of Dr. Ruoslahti (senior author of both studies) at Sanford Burnham Prebys, discovered a peptide—a small chain of amino acids, the building blocks of proteins—that specifically targeted injured areas of the brain in mice. The peptide, named CAQK, was identified through a large-scale screening technique known as peptide-phage display, which allows the selection of molecules with affinity for specific tissues.

In that earlier study, CAQK was used as a “vehicle” to deliver drugs directly to the damaged area. However, in their new work, the researchers went a step further and demonstrated that the CAQK peptide itself has therapeutic effects.

Evidence of Therapeutic Effects

To evaluate its therapeutic activity, the peptide was first administered intravenously shortly after a moderate or severe traumatic brain injury, and it was observed that the peptide accumulated in the injured brains of mice and pigs (the latter having brains more similar to humans than mice). Furthermore, it was found that the peptide binds to special molecules called glycoproteins (proteins attached to sugars), which become more abundant after an injury and are part of the extracellular matrix—a supporting network that surrounds brain cells.

Treatment of mice with traumatic brain injury using this peptide resulted in a reduction in lesion size compared to control mice. “We observed less cell death and lower expression of inflammatory markers in the injured area, indicating that CAQK alleviated neuroinflammation and its secondary effects. Behavioral and memory tests conducted after treatment also showed improvement in functional deficits, with no evident toxicity,” explains the study’s first author, Dr. Mann.

The study’s results demonstrate that the CAQK peptide can help repair the damaged area, highlighting its potential therapeutic applications following trauma. “What’s exciting is that, in addition to proving highly effective, it’s a very simple compound—a short peptide that is easy to synthesize safely at large scale. Peptides with these characteristics show good tissue penetration and are non-immunogenic,” concludes Scodeller.

Reference: “A neuroprotective tetrapeptide for treatment of acute traumatic brain injury” by Aman P Mann, Sazid Hussain, Pablo Scodeller, Hope N B Moore, Elan Sherazee, Rachel M Russo and Erkki Ruoslahti, 1 October 2025, EMBO Molecular Medicine.
DOI: 10.1038/s44321-025-00312-5

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