New research from Cincinnati Children’s suggests that treatment with antioxidants may help reduce behavioral issues linked to the genetic nervous system disorder neurofibromatosis 1 (NF1) and an associated condition, Costello syndrome.

Findings were posted Sept. 12 in Cell Reports. The study, led by Nancy Ratner, PhD, Division of Experimental Hematology and Cancer Biology, shows that defects in the NF1/Ras molecular pathway, which cause the disorders, trigger production of harmful oxidative nitric oxide molecules in the oligodendrocyte glial brain cells of mice.

How the disorder affects myelin

Glial cells produce myelin, which provides an insulating sheath along nerve fibers. Increased production of nitric oxide in the tested mice disrupted the tight structure of proteins and related components that make up the myelin sheath. It also damaged vasculature surrounding astrocyte cells and endothelial tissue. Combined, these changes altered the permeability of the blood-brain barrier.

Affected mice had enlarged mutant white brain matter, enlarged optic nerves and exhibited hyperactive behavior. Levels of nitric oxide synthases were significantly up-regulated in the mutant white matter, the study reports.

Hyperactivity is present in up to 60 percent of people with NF1or Costello syndrome.

Improved hyperactive behaviors

“Our data provide a potential cellular and molecular mechanism of Rasopathy brain abnormalities, and we show that treatment with a broad spectrum antioxidant reverses the disruption of affected tissues and improves hyperactive behavior,” Ratner says. “It will be interesting to see if people with Rasopathy exhibit the same white matter enlargement and cellular features we identified in our laboratory tests.”

To treat the mice, researchers added the broad-spectrum antioxidant N-Acetyl Cysteine (NAC) to the animals’ drinking water. After six weeks of exposure to NAC, abnormal cellular and tissue structure were reversed and hyperactive behavior subsided. The reversal of symptoms was more pronounced in the Costello mice than the NF1 mice.

When researchers gave the same antioxidant treatment to normal, wild-type mice, it caused the blood brain barrier to open and harmed the compact structure of myelin. Researchers said this shows high levels of antioxidant treatment without elevated reactive oxygen levels can be detrimental.

The study sheds new light on the molecular processes that may cause people with NF1 to suffer from a number of cognitive and behavioral deficits. However, authors cautioned that laboratory studies involving mouse models do not necessarily translate to treatment of human disease. Additional study is needed.