In 2015, a team of scientists at the University of Chicago found that hypertension drug Wytensin (guanabenz) could prevent myelin loss and alleviate symptoms of multiple sclerosis in animal models. Now, that team has returned with data showing that a similar drug with the same myelin-protecting mechanism could serve as a safer alternative.
MS is triggered by an autoimmune attack on myelin-producing cells called oligodendrocytes. Once these cells are damaged, myelin—the protective sheath around nerve cells—degenerates and eventually causes nerve-cell death.
In a recent study published in the journal Brain, a team led by Brian Popko, Ph.D., showed that a small-molecule derivative of Wytensin called Sephin1 could “delay the loss of myelin and postpone the onset of debilitating disease” in a mouse model of MS, Popko said in a statement.
Popko was also the senior author of a 2015 Nature Communications study on Wytensin. At that time, Popko and colleagues demonstrated that in mouse models of MS, Wytensin appeared to enhance the integrated stress response, a protective mechanism that maintains cellular proteostasis—or the balance of proteins—and protects cells from inflammatory damage. The animals treated with Wytensin were protected against oligodendrocyte and myelin loss and saw delayed onset and reduced severity of MS symptoms.
However, Wytensin has one major shortfall: Due to its affinity to the alpha-2 adrenergic receptor, it can cause side effects such as drowsiness, lethargy and even coma at high doses.
So for the new study, Popko’s team focused on Sephin1. Here’s how his team believes it works: As part of the integrated stress response, an enzyme called eukaryotic translation initiation factor 2α (eIF2α) is "phosphorylated," or modified in a way that allows the synthesis of proteins that guard against inflammation. Sephin1 prolongs that protective response by selectively inhibiting a gene called PPP1R15A, they believe.
And Sephin1 plays another critical role, they added. “By protecting oligodendrocytes and diminishing demyelination we also reduce the generation of myelin debris,” Popko said in a statement. “The decreased exposure to myelin fragments should also limit the auto-immune response.”
The findings echoed a 2015 study published in Science. In that research, a University of Cambridge-led team showed that Sephin1 didn’t cause the adverse effects of Wytensin. It enhanced the integrated stress response in mice, preventing the protein-misfolding diseases Charcot-Marie-Tooth 1B and amyotrophic lateral sclerosis.
Current MS treatments focus mainly on limiting the immune system’s attack, but they can cause side effects including brain infections. So restoring the myelin sheath could represent a better approach, the UChicago team figured. And they’re not alone. Researchers at Cincinnati Children’s Hospital, for example, previously reported that a microRNA called miR-219 could restore the function of oligodendrocytes.
Because Sephin1’s mechanism is different from traditional immune-modulating MS therapies, Popko’s team believes a combination treatment may be promising. In their new study, they found that adding Sephin1 to the standard MS therapy interferon-beta did produce some benefits. For example, the animals that received the combo treatment experienced an even more dramatic decline in disease development than those that got Sephin1 alone, the team reported.
“These data indicate that combining Sephin1 and [interferon-beta] provides an additive therapeutic benefit in ameliorating and delaying the symptoms of [MS],” the researchers wrote in the study.