UCLA Health identifies first drug to pharmacologically replicate stroke rehabilitation effects
Researchers say the discovery could address the lack of drugs available to treat the disease process of stroke recovery, though further studies are required before potential human trials.
UCLA Health researchers have identified the first drug capable of fully reproducing the effects of physical stroke rehabilitation in model mice. The study, published in Nature Communications, found that the compound DDL-920 restores lost brain connections and gamma oscillations in parvalbumin neurons, leading to significant recovery in movement control. This discovery represents a potential shift from relying solely on modestly effective physical therapy to a molecular medicine approach that pharmacologically mimics rehabilitation outcomes.
Stroke remains the leading cause of adult disability because most patients do not fully recover, and current treatments rely heavily on physical rehabilitation which is often limited by the intensity patients can sustain. Unlike fields such as cardiology, infectious disease, or cancer, there are currently no drugs available to treat the disease process of stroke recovery itself. Dr S. Thomas Carmichael, the study's lead author and professor and chair of UCLA Neurology, noted that rehabilitation after stroke is limited in its actual effects because most patients cannot sustain the rehab intensity needed for recovery.
The UCLA 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 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, resulting in brain networks that do not fire together for things like movement and gait.
The researchers 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 behaviour, such as movement. Stroke causes the brain to lose gamma oscillations, but 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, and second, it identifies a unique drug target in this rehab brain circuity to promote recovery by mimicking the main effect of physical rehab.
Further studies are required to assess safety and efficacy before potential human trials can begin. The specific duration of the recovery observed in the mouse models is not detailed in the provided text, and the precise dosage and administration protocols for DDL-920 in the animal study are not specified. The extent to which the drug's mechanism translates directly to the complex human brain environment remains unproven, though the findings offer a promising new direction for treating the disease process of stroke recovery.
