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.
