APRIL 2, 2021 BY MARTA FIGUEIREDO PHD
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Prolonging a cellular defense mechanism shown to restore myelin — the protective sheath around nerve cell fibers that is lost in multiple sclerosis (MS) — may be key to treating the neurodegenerative disease, a study in MS mouse models suggests.
That defense mechanism, called integrated stress response (ISR), helps protect both mature and newly formed oligodendrocytes, or myelin-producing cells, from the damaging inflammatory environment that characterizes brain lesions in MS.
The researchers said that “ISR enhancement may provide reparative benefit to MS patients” by increasing myelin thickness.
“Prolonging the integrated stress response helps the cells withstand the adverse inflammatory environment and gives the cells more time to recover,” Yanan Chen, MD, PhD, the study’s lead author at the Northwestern University Feinberg School of Medicine, said in a university press release.
In addition, combining this approach — achieved with a small molecule called Sephin1 — with bazedoxifene, an investigational therapy shown to promote oligodendrocyte maturation, resulted in the restoration of the myelin sheath to pre-lesion levels.
These findings highlight the therapeutic potential of ISR-promoting interventions, alone and in combination with myelin repair-promoting treatments, in MS, the team noted.
The study, “Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment,” was published in the journal eLife.
In the brain, myelin damage attracts immature, stem-like cells called oligodendrocyte precursor cells (OPCs) to the lesion site, where they mature into oligodendrocytes — myelin-producing cells capable of restoring the myelin sheath.
Despite the presence of OPCs in MS lesions, remyelination (myelin repair) is incomplete or absent. Notably, the complex inflammatory environment present in MS lesions is “considered a major contributor to impaired remyelination,” the researchers wrote.
While several molecules have been shown to promote oligodendrocyte maturation and/or remyelination in preclinical models, most of these models involve non-inflammatory myelin loss, failing to closely mimic what happens in MS.
“The inflammatory environment [in MS] is far from ideal for the repair process; there are debris from previously present myelin, infiltrating [immune cells] and myriad proinflammatory [molecules] not normally present in the brain,” said Brian Popko, PhD, the study’s senior author.
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