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Researchers here report on their efforts to interfere in a mechanism causing loss of the myelin that sheathes nerves. The driving goal is to produce a therapy for the severe demyelinating disease of multiple sclerosis rather than to reverse the lesser degree of myelin loss that occurs for everyone in later life. The animal evidence suggests that it may also prove to be useful in the general population of older individuals, however, which is promising. Loss of myelin is thought to contribute to some fraction of age-related loss of cognitive function, and so reversing that loss is an important goal.

Oligodendrocytes (OLs) are responsible for producing myelin sheaths that wrap around cable-like parts of nerve cells called axons, much like the plastic insulation around a wire. When the protective myelin gets damaged, be it by disease or the wear and tear of age, nerve signaling gets disrupted. Depending on where the damaged nerves lead, the disruptions can affect movement, vision, thinking and so on.

Analysis of stored autopsy tissues revealed that OLs within multiple sclerosis (MS) lesions lacked an activating histone mark called H3K27ac, while expressing high levels of two other repressive histone marks H3K27me3 and H3K9me3 associated with silencing gene activity. The research team scoured a library of hundreds of small molecules known to target enzymes that could modify gene expression and influence the silenced OLs. The team determined that the compound ESI1 (epigenetic-silencing-inhibitor-1) was nearly five times more powerful than any other compounds they considered.

The compound tripled the levels of the desired H3K27ac histone mark in OLs while sharply reducing levels of the two repressive histone marks. In both aging mice and mice mimicking MS, the ESI1 treatment prompted myelin sheath production and improved lost neurological function. Testing included tracking gene activation, measuring the microscopic new myelin sheaths surrounding axons, and observing that treated mice were quicker at navigating a water maze.

Link: https://www.eurekale...eleases/1043326

View the full article at FightAging