MIND
November 29, 2013

Drug Moonlights As Anti-Seizure Med

A blood pressure medication already approved for human use may prevent seizures in those with liver disease.

When a person's liver is not working properly, the risk of having a seizure goes way up. Millions of people with chronic liver problems, whether because of hepatitis B, alcoholism, or an inherited metabolic disorder, also contend with seizures.

Ammonia appears to be the point of connection between liver problems and seizures. Now researchers have found an unlikely, but promising new treatment: a drug normally used to treat high blood pressure.

Once inside the brain, ammonia works as an electrical trigger, keeping brain cells in a state of heightened excitability. This can lead to tremors and seizures.

Using advanced imaging techniques that directly peer into the brains of living mice, scientists from the University of Rochester Medical Center discovered how ammonia causes seizures in the brain. The chemical interacts with key molecular gatekeepers on the surface of brain cells that normally guard the flow of charged particles (ions) into and out of the cells.

When ammonia accumulates, these gatekeepers are kept on “overdrive,” allowing too many ions to flow into brain cells at once. This chemical imbalance leads to a spike in the electrical activity inside the cells and to the development of seizures.

People with malfunctioning livers cannot process ammonia, a common waste product of protein breakdown. As a result, ammonia builds up in the bloodstream as a gas and makes its way through the blood into brain tissue.

Once inside the brain, ammonia works as an electrical trigger, keeping brain cells in a state of heightened “excitability.” This can lead to tremors and seizures, which in the long-term can cause permanent neurological impairment.

Bumetanide or Bumex®, a drug normally used to treat high blood pressure, has shown some promise for patients with impaired livers and metabolic problems. The drug seems to reduce seizures by acting on the same biological pathways associated with chronic liver disease.

The researchers found that bumetanide works by removing the flow of ions through the same molecular gatekeepers targeted by ammonia. By blocking the process altogether, bumetanide reduced seizure incidence and prolonged survival in mice with an overabundance of ammonia.

The results bode well for humans with metabolic disorders and liver impairments who also suffer from chronic seizures. Bumetanide is already an approved drug and is unlikely to cause any additional side effects in the brain.

“The fact that bumetanide is already approved for use gives us a tremendous head start in terms of developing a potential treatment for this condition,” lead author Maiken Nedergaard said in a statement.

This study is published in advance of print in the online version of Nature Medicine.

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