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.
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
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.