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June 27, 2017
The preclinical study shows that the anti-muscarinic drug, approved by the U.S. Food and Drug Administration to treat overactive bladder, can boost myelination by targeting human oligodendrocyte progenitor cells.
“We have identified a way to improve human myelination,” says lead author Fraser J. Sim, PhD, assistant professor of pharmacology and toxicology and a faculty member in the UB Neuroscience Program.
The promising results have prompted Sim and his colleagues to seek funding for a small human trial.
In MS and other neurological diseases, myelin — the fatty insulator that enables communication between nerve cells — is damaged.
Some remyelination occurs initially, but this ability to regenerate dissipates as the disease progresses and the patient ages.
Sim’s prior research on stem cells and myelination found that a critical phase of remyelination fades with age.
“Our hypothesis is that in MS, the oligodendrocyte progenitor cells seem to get stuck,” says Sim. “When these cells don’t mature properly, they don’t differentiate into myelinating oligodendrocytes.”
Sim and his colleagues first characterized the molecular pathways governing the differentiation of human oligodendrocyte progenitor cells. They then worked to identify drug candidates that would promote differentiation and myelin production.
They found the opposite result — that differentiation was completely blocked — when they activated a muscarinic type 3 receptor on human oligodendrocyte progenitor cells.
“So we asked: Could we boost differentiation if we had something that blocks instead of activates this receptor?” Sim says.
The researchers then transplanted human oligodendrocyte progenitor cells into mice that could not make myelin. When they administered solifenacin to these mice, differentiation and myelin synthesis increased.
The researchers also found improved response to auditory signals in treated animals — a sign that the remyelination improved physical function.
They chose to test auditory brainstem response because myelin affects the rate of brain wave activity in response to sounds, Sim explains. To conduct the tests, Sim partnered with co-author Richard J. Salvi, PhD, SUNY Distinguished Professor of communicative disorders and sciences, also a faculty member in the UB Neuroscience Program.
The tests result in a readout with waves that should show a particular time pattern, since it takes a certain amount of time for a signal to travel from the ear and through the brain, says Sim.
“When there isn’t enough myelin, the signaling slows down; if you add myelin, you should see the signals speed up.”
Reposted from University of Buffalo
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