Hypertension Medicine May Have Application in Fragile X Syndrome, Mouse Study Shows

Originally approved for hypertension, the injectable medicine bumetanide was able to correct an imbalance in nerve cells that underlies sensory problems linked to fragile X syndrome, a new mouse study shows.

The study “Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in fragile X mice” was published in the journal Molecular Psychiatry.

Some fragile X syndrome or autistic children have alterations in sensory processing. “A lot of patients don’t like loud sounds or don’t like to be touched,” Anis Contractor, study lead author at Northwestern University said in a press release.

“When I talk to parents of children with fragile X, some tell me these sensory issues lead to many other problems, because the kids are withdrawn or socially isolated,” he added.

In a mouse model mimicking human fragile X (FXS mouse) development of the brain region that receives all the sensory input from the rest of the body — the somatosensory cortex — is delayed.

“The mouse models give us a window into the human disorder. Although mouse brain development is not a completely faithful model of humans, there certainly are parallels,” Contractor said.

Previous work at Contractor’s lab has shown that high concentrations of intracellular chloride in nerve cells leads to an abnormal cellular excitation, resulting in deviations from the normal timing of key development processes that occur early in the brain. As a result, the normal wiring of the brain is affected.

Contrary to normal mice where, for example, a single whisker activates a single cluster of cells in the brain’s sensory system, in the FXS mouse multiple nerve cells are activated, creating a hyper-excited state of brain activation.

“The activity bleeds to other clusters of cells, activating more cells than it normally would,” Contractor explained.

The team tested bumetanide, originally developed and approved for hypertension, to correct chloride imbalances and reverse nerve cell hyper-excitability.

“It’s actually not used very much anymore, because there are better drugs on the market now. But in addition to its effect on blood pressure it can affect neuronal chloride transporters and the influx of chloride into the cell,” Contractor said.

FXS mice treated with bumetanide (trade names Bumex or Burinex) for two weeks after birth had normal intracellular chloride levels and a normal development of the brain’s excitatory network.

These results demonstrate that, when given early during development, bumetanide “can rectify developmental synaptic phenotypes that are prominent during critical period in the somatosensory cortex,” researchers wrote.

Importantly, it also corrected the sensory problems observed in adult mice. “It is possible that correcting chloride or correcting neurotransmitter signaling in humans could also have the same effect,” Contractor said.