Medically Reviewed By Vikas Londhe M.Pharm (Pharmacology)
In a landmark study published in Nature Communications, University of California, Los Angeles (UCLA) researchers identified the first drug that is able to promote stroke rehabilitation by reestablishing connections between affected brain cells. Drug DDL-920, which specifically targets parvalbumin interneurons, a critical type of brain cell that has been affected during stroke and that plays a key role in neural circuit function and recovery after stroke.
Stroke
Stroke is a life-threatening condition where brain cells are damaged, depending on the severity of the stroke. Strokes are of two types: ischemic stroke and hemorrhagic stroke. However, a mild stroke does not affect the patient seriously, but severe ischemic and hemorrhagic strokes result in serious complications like loss of sensation in half of the body, which severely affects patients’ abilities to do activities of daily living (ADL). Hence, stroke is considered to be the leading cause of long-term disability, often leaving survivors with impaired motor functions.
One of the biggest challenges in the treatment of stroke is the inability of the brain to fully recover. This is because brain cells die during the stroke, and some connections between neurons are lost. These connections were unknown till date, which is why no treatments were developed in the past to restore these connections. Stroke patients were fully dependent on physical rehabilitation and other prophylactic medications to prevent further complications like seizures and infections.
What does the new research say
The UCLA team, led by Dr. S. Thomas Carmichael and Naohiko Okabe, researched to determine post-stroke brain rehabilitation science and possible pharmacological compounds that allow patients to recover the same as physical therapy does.
The first scientists discovered how the brain performs motor skills or motor activity post-stroke during physical therapy. Scientists have found out that to learn new motor skills, like pressing a lever, certain brain cells called interneurons form connections. It reduces connections made by one type of cell, called somatostatin interneurons, and increases connections made by another type of cell, called parvalbumin interneurons. This shows that different brain cells play special roles in helping people recover movement skills after a stroke, especially for complex tasks. However, scientists didn’t fully understand which brain circuits were involved, how important they were, or if a drug could copy the effects of rehabilitation therapy in the past. In this study, the scientist found that brain circuits involving parvalbumin interneurons and stroke-affected neurons help recovery by making brain activity more synchronized. These findings suggest possible drug targets that could mimic the effects of rehabilitation.
To understand the role of this type of neuronal circuit in functional recovery induced by rehabilitation, the scientist developed a mouse model to study how the brain functions during rehabilitation and how certain circuits, like the parvalbumin interneuron-stroke-affected neuron circuit, play a role in rehabilitation.
In this study, scientists knew that certain brain cells called parvalbumin interneurons connect more with stroke-affected neurons during rehabilitation, so they wanted to see if rehabilitation turns on this connection. To check this, scientists looked at whether rehabilitation causes changes in brain activity and flexibility in an area called RFA. Scientists did this by measuring special “activity” genes (Zif268 and FosB) and looking at structures called perineuronal nets, which can limit how flexible parvalbumin cells are. Scientists found that rehabilitation increased the activity of both types of neurons and made stroke-affected neurons even more active. Rehabilitation also made fewer parvalbumin cells covered by these nets, meaning they could change and adapt more easily. These results show that rehabilitation wakes up and boosts the flexibility of these brain circuits.
New pharmacologically active compound for stroke
As scientist discovered what are the things happened in brain during rehabilitation physical therapy and what are the circuits involved in it. Now scientist wants to check some pharmacological compounds which can target these sites and produce rehabilitation like effect.
Scientist tested two different compounds
AUT00201, which boosts the activity of certain proteins called Kv3.1 ion channels mostly found in Parvalbumin interneurons.
DDL-920, developed in UCLA lab of Varghese John, which reduces the activity of a specific type of GABA receptor called α1β2δ GABAAR that normally, slows down Parvalbumin interneurons.
The special GABA receptors scientist targeted are mainly found on Parvalbumin interneurons. They are different from similar receptors found on other brain cells like granule cells, pyramidal cells, or cerebellar cells.
Boosting Kv3.1 channels makes Parvalbumin interneurons fire faster and more efficiently. Reducing GABAARδ activity lowers the “brake” on these cells, making them more active. These changes help adjust the brain’s gamma Oscillation, which are important for many brain functions.
Scientist gave the drugs by mouth to make them easier to use in future treatments for people. Scientist confirmed that the targets of these drugs (Kv3.1 channels and GABAARδ receptors) are mainly present on Parvalbumin interneurons in both healthy and stroke-affected brains.
To see if the drugs activated Parvalbumin interneurons, they gave just one dose. As expected, both AUT00201 and DDL-920 increased the activity of a marker called Zif268 in Parvalbumin interneurons, showing that the cells became more active. However, only DDL-920 caused a significant increase.
In a stroke recovery study, scientist started drug treatments three days after the stroke happened. Then tested how well the animals could use their forelimbs to grab small pasta pieces and how well they could walk across a grid without slipping.
Neither drug caused bad side effects like weight loss or movement problems.
Animals that had strokes and were given either the vehicle (placebo) or AUT00201 had trouble picking up the pasta pieces.
In contrast, animals treated with DDL-920 completely recovered their ability to pick up the pasta.
Both drugs also helped the animals recover faster in the walking test.
Overall, these results show that drugs like these specially DDL-920 can help the brain heal after a stroke in a way similar to what is seen with physical rehabilitation.
Why This Discovery Matters
Current post stroke treatment includes physical rehabilitation which relies heavily on physical therapy; however, full function of the body cannot be restored by this therapy. DDL-920 represents a paradigm shift by directly targeting the biological mechanisms of recovery.
Dr. Carmichael, lead author and professor and chair of UCLA Neurology, said that “This is the first drug designed to repair neural circuits after stroke.” “Instead of just managing symptoms, we’re addressing the root cause of disability by helping the brain heal itself.”
Next Steps: Clinical Trials and Future Applications
The UCLA team is now preparing for human clinical trials, which could begin within the next two years. If successful, DDL-920 can become a cornerstone of post-stroke treatment, benefiting millions of survivors worldwide. Along with stroke, this newfound mechanism and new targets can be beneficial in treating other conditions, such as Traumatic brain injury (TBI), Spinal cord injuries, and Neurodegenerative diseases like Alzheimer’s and Parkinson’s
Conclusion
The development of DDL-920 marks a historic milestone in neuroscience and stroke rehabilitation. By unlocking the brain’s innate ability to rewire itself, this drug could transform recovery for stroke survivors, offering new hope where options were once limited.
References:
1. UCLA discovers first stroke rehabilitation drug to re-establish brain connections in mice, UCLA Newsroom, 20 March 2025, available from https://newsroom.ucla.edu/releases/ucla-discovers-first-stroke-rehabilitation-drug-to-reestablish-brain-connections-in-mice
2. Okabe, N., Wei, X., Abumeri, F. et al. Parvalbumin interneurons regulate rehabilitation-induced functional recovery after stroke and identify a rehabilitation drug. Nat Commun 16, 2556 (2025). https://doi.org/10.1038/s41467-025-57860-0
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