Key takeaways
- UCLA researchers identified a loss of brain connections that stroke produces that are remote from the site of the stroke damage.
- The UCLA team found that some of the connections lost after stroke occur in a cell called a parvalbumin neuron, which helps a brain rhythm function.
- The researchers found that a drug called DDL-920, developed in the UCLA lab of Varghese John, produced significant recovery in movement control in mice.
A new study by UCLA Health has discovered what researchers say is the first drug to fully reproduce the effects of physical stroke rehabilitation in model mice.
The findings, published in Nature Communications, tested two candidate drugs derived from their studies on the mechanism of the brain effects of rehabilitation, one of which resulted in significant recovery in movement control after stroke in mice.
Stroke is the leading cause of adult disability because most patients do not fully recover from the effects of stroke. There are no drugs in the field of stroke recovery, requiring stroke patients to undergo physical rehabilitation, which has shown to be only modestly effective.
“The goal is to have a medicine that stroke patients can take that produces the effects of rehabilitation,” said Dr. S. Thomas Carmichael, the study’s lead author and professor and chair of UCLA Neurology. “Rehabilitation after stroke is limited in its actual effects because most patients cannot sustain the rehab intensity needed for stroke recovery.
“Further, stroke recovery is not like most other fields of medicine, where drugs are available that treat the disease — such as cardiology, infectious disease or cancer,” Carmichael said. “Rehabilitation is a physical medicine approach that has been around for decades; we need to move rehabilitation into an era of molecular medicine.”
In the study, Carmichael and his team sought to determine how physical rehabilitation improved brain function after a stroke and whether they could generate a drug that could produce these same effects.
Working in laboratory mouse models of stroke and with stroke patients, the UCLA researchers identified a loss of brain connections that stroke produces that are remote from the site of the stroke damage. Brain cells located at a distance from the stroke site get disconnected from other neurons. As a result, brain networks do not fire together for things like movement and gait.
The UCLA team found that some of the connections that are lost after stroke occur in a cell called a parvalbumin neuron. This type of neuron helps generate a brain rhythm, termed a gamma oscillation, which links neurons together so that they form coordinated networks to produce a behavior, such as movement. Stroke causes the brain to lose gamma oscillations. Successful physical rehabilitation in both laboratory mice and humans brought gamma oscillations back into the brain and, in the mouse model, repaired the lost connections of parvalbumin neurons.
Carmichael and the team then identified two candidate drugs that might produce gamma oscillations after stroke. These drugs specifically work to excite parvalbumin neurons.
The researchers found one of the drugs, DDL-920, developed in the UCLA lab of Varghese John, who coauthored the study, produced significant recovery in movement control in mice.
This study has two major areas of impact: First, it identifies a brain substrate and circuity that underlies the effect of rehabilitation in the brain. Second, the paper then identifies a unique drug target in this rehab brain circuity to promote recovery by mimicking the main effect of physical rehab.
Further studies are needed to understand the safety and efficacy of DDL-920 before it could be considered for human trials.
Contact
Will Houston
310-948-2966
whouston@mednet.ucla.edu
UCLA discovers first stroke rehabilitation drug to reestablish brain connections in mice | UCLA
The human brain, with its vast network of interconnected neurons, possesses an extraordinary capacity for adaptation and recovery. Yet, when a stroke disrupts this delicate circuitry, the consequences can be devastating—paralysis, loss of speech, and impaired cognition often persist despite intensive rehabilitation. For decades, recovery has depended largely on physical therapy, which works by gradually retraining the brain to form new connections. Now, researchers at University of California, Los Angeles have identified a compound, DDL-920, that appears to replicate key aspects of this rehabilitation process at a molecular level—at least in preclinical studies involving mice.
This discovery represents a profound shift in how scientists think about recovery after neurological injury. Rather than relying solely on external physical stimulation to guide neural rewiring, DDL-920 suggests that it may be possible to pharmacologically trigger the same restorative processes within the brain itself. The implications are far-reaching, pointing toward a future where recovery from stroke is not only faster, but also more accessible to patients who are unable to undergo intensive therapy.
The Biological Challenge of Stroke Recovery
A stroke interrupts blood flow to regions of the brain, depriving neurons of oxygen and nutrients. The result is cell death and, more critically, the disruption of neural circuits that govern movement and coordination. Even when some neurons survive, their connections—synapses—may be weakened or lost.
Recovery depends on a phenomenon known as Neuroplasticity, the brain’s ability to reorganize itself by forming new synaptic connections. Physical rehabilitation leverages this property by repeatedly activating specific motor pathways, encouraging the brain to rewire itself around damaged regions.
However, this process is:
- Slow and labor-intensive
- Highly dependent on patient participation
- Often incomplete, especially in severe cases
The central challenge has been finding a way to enhance or accelerate neuroplasticity without relying exclusively on behavioral training.
DDL-920: A Pharmacological Shortcut to Rehabilitation
DDL-920 emerges as a candidate solution to this challenge. In controlled laboratory studies, the compound demonstrated the ability to restore motor function in mice following stroke, even in the absence of extensive physical rehabilitation.
What makes DDL-920 particularly compelling is not just the observed recovery, but how it achieves this effect. Rather than acting as a simple neuroprotective agent, the drug appears to reconstruct functional neural pathways, effectively mimicking the outcomes of rehabilitation at the synaptic level.
Technical Mechanism: Rebalancing Neural Circuits
To understand DDL-920’s impact, it is necessary to examine the balance between two fundamental types of neurons:
- Excitatory neurons: Promote neural activity
- Inhibitory neurons: Regulate and suppress excessive activity
A critical subset of inhibitory neurons expresses a protein called Parvalbumin. These parvalbumin interneurons play a key role in synchronizing neural circuits and maintaining stability.
Post-Stroke Disruption
After a stroke:
- Inhibitory signaling often becomes dysregulated
- Neural circuits lose coordination
- Motor pathways fail to activate properly
This imbalance prevents effective communication between brain regions, particularly those involved in movement.
DDL-920’s Mode of Action
Research indicates that DDL-920 works by modulating inhibitory synaptic transmission, specifically targeting parvalbumin interneurons.
Key Effects:
- Restoration of Inhibitory Balance
- Re-establishes proper timing and coordination of neural firing
- Reactivation of Dormant Pathways
- Enables previously disconnected motor circuits to function again
- Promotion of Synaptic Plasticity
- Enhances the brain’s ability to form and strengthen new connections
At a systems level, the drug appears to reopen a “plasticity window”, a state in which the brain becomes more receptive to rewiring—similar to what occurs during early development or intensive rehabilitation.
Experimental Evidence in Mice
In preclinical models, mice that experienced stroke-induced motor deficits were treated with DDL-920. The results were striking:
- Significant improvement in motor coordination
- Restoration of movement patterns comparable to rehabilitated mice
- Evidence of reconnected neural pathways in motor cortex circuits
Notably, these improvements occurred without the same level of physical training typically required, suggesting that the drug itself was driving the recovery process.
Circuit-Level Interpretation
From a computational neuroscience perspective, the brain can be viewed as a network:Output (movement)=f(input signals,network connectivity)
Stroke disrupts this connectivity. Rehabilitation attempts to rebuild it through repeated input stimulation. DDL-920, by contrast, appears to modify the network parameters directly, restoring functional connectivity without requiring extensive external input.
This represents a shift from:
- Behavior-driven plasticity → Chemistry-driven plasticity
Implications for Human Medicine
If the effects observed in mice translate to humans, DDL-920 could transform stroke recovery in several ways:
1. Reduced Dependence on Intensive Therapy
Patients who cannot participate in rigorous rehabilitation—due to age, severity, or access—could still achieve meaningful recovery.
2. Accelerated Recovery Timelines
Pharmacologically induced plasticity may shorten the time required to regain function.
3. Combination Therapies
DDL-920 could be used alongside physical therapy to amplify its effectiveness, creating a synergistic effect.
Limitations and Challenges
Despite its promise, several critical hurdles remain:
1. Translation from Mice to Humans
Neural complexity differs significantly between species. What works in mice may not fully replicate in human brains.
2. Safety and Side Effects
Modulating inhibitory circuits carries risks, including:
- Seizures (if inhibition is reduced too much)
- Cognitive side effects
3. Precision Targeting
Ensuring the drug affects only relevant circuits without disrupting others is a major challenge.
Broader Scientific Significance
Beyond stroke recovery, DDL-920 highlights a broader paradigm:
The possibility of pharmacologically controlling neural plasticity
This could have implications for:
- Neurodegenerative diseases
- Traumatic brain injury
- Psychiatric disorders involving circuit dysfunction
It also reinforces the idea that the brain is not a static organ, but a dynamic system that can be reprogrammed under the right conditions.