Ambien Shown to Speed Stroke Recovery in Mice
Mice that had strokes rebounded significantly faster if they received low doses of Zolpidem, more commonly known as Ambien.
According to researchers at the Stanford University School of Medicine, Ambien has long been approved by the U.S. Food and Drug Administration for treating insomnia.
But it has never before been shown to enhance recovery from stroke, said Gary Steinberg, M.D., Ph.D., a professor and chair of neurosurgery at the medical school.
Each year, Americans have about 800,000 strokes, the nation’s largest single cause of neurologic disability, racking up an annual tab of about $74 billion in medical costs and lost productivity, according to the researchers.
Within three to six months, at least 90 percent of all the recovery a stroke patient is likely to experience takes place. No pharmaceutical therapy has been shown to improve recovery after the stroke.
In fact, no effective treatments during the recovery phase exist, other than physical therapy, which has been shown to be only marginally successful, the researchers noted.
Steinberg and co-author Tonya Bliss, Ph.D., a senior research scientist, attributed zolpidem’s effectiveness to its enhancement of a type of nerve-cell signaling activity whose role in recovery unexpectedly appears beneficial.
In the study, this signaling was bolstered even though the drug was given at doses well below those at which it exerts its sedative effect.
Nerve cells signal to one another with neurotransmitters. When neurotransmitters are secreted by the nerve cell sending the signal, they dock in receptors situated on abutting nerve cells’ surfaces. Most of this signaling takes place at specialized junctions called synapses, which feature high concentrations of neurotransmitters from the upstream cell that activate receptors on the downstream cell.
Neurotransmitters can be excitatory, triggering an impulse in the receiving nerve cell. Or they can be inhibitory, temporarily preventing the receiving nerve cell from propagating any impulses. The roughly one-fifth of all nerve cells in the brain that are inhibitory mainly do their job by secreting a neurotransmitter called GABA, the researchers explain.
While the bulk of GABA signaling takes place at synapses, scientists have learned that nerve cells can also feature GABA receptors elsewhere on their outer surfaces. These are called extrasynaptic receptors.
In 2010, other researchers reported that extrasynaptic GABA signaling impeded stroke recovery in an animal model. But until the Stanford study, nobody had looked into the impact on stroke recovery of the far more common synaptic GABA signaling, the scientists said.
To do that, Steinberg, Bliss and their colleagues conducted a series of anatomical, physiological and behavioral experiments.
Using a high-resolution visualization method, the scientists examined a region of the mouse brain near the area that had been destroyed by stroke and is known to rewire afterward. They saw a transient increase in the number of GABA synapses. This increase peaked at about a week after the stroke and subsided to baseline levels by one month after the stroke’s damage has been done.
The rise and fall of synapse-associated GABA receptors was restricted to a particular layer of the cerebral cortex that sends output to the spinal cord and to other brain areas, the researchers reported.
Intrigued by this anatomical finding, the scientists looped in their colleague John Huguenard, Ph.D., professor of neurology and neurological sciences and co-author of the study. Electrophysiological experiments in Huguenard’s lab confirmed that the transitory increase in GABA synapse numbers was matched by an increase, followed by a decline to baseline levels, in synaptic GABA signaling, confirming that the synapses were indeed functional.
To determine whether the transient increase in post-stroke synaptic GABA signaling was beneficial — and, if so, whether it could be enhanced — the researchers turned to zolpidem, which works by enhancing synaptic GABA signaling.
They induced one of two different types of strokes in mice — one type severely damages sensory ability, the other deeply impairs movement — then put the mice on a regimen of either zolpidem or a control solution that did not contain the drug.
The scientists administered the drug in sub-sedative doses. They wanted to see how the mice would perform on tests of sensory ability and motor coordination, so the mice needed to be fully awake.
The researchers then subjected the mice to two kinds of tests. One measured the speed with which they removed a patch of adhesive tape from one of their paws (mice ordinarily are quick to do so). The other test gauged their ability to traverse a horizontal rotating beam.
In almost every case, zolpidem-treated mice recovered at a faster rate than the other mice. It took about a month, for example, for mice not given zolpidem to fully recover their stroke-impaired ability to notice the tape stuck to their paw. Mice given zolpidem recovered that ability within a few days of treatment.
The Stanford researchers intend to test the drug in other animals, as well as to experiment with different dose sizes and timing, before proceeding to clinical trials.
“Before this study, the thinking in the field was that GABA signaling after a stroke was detrimental,” said Steinberg. “But now we know that if it’s the right kind of GABA signaling, it’s beneficial. And we’ve identified an FDA-approved drug that decisively promotes the beneficial signaling.”
The study was published in Brain.
Wood, J. (2018). Ambien Shown to Speed Stroke Recovery in Mice. Psych Central. Retrieved on September 20, 2020, from https://psychcentral.com/news/2015/12/20/ambien-improves-stroke-recovery-in-mice/96456.html