Drug May Blunt Neurological Damage Caused by Liver Failure

Individuals with impaired liver function are unable to remove ammonia – a by-product of normal cellular activity – from their bodies fast enough.  This result is a host of neurological problems, including seizures, for which doctors have no effective treatment.  A new study shows that an existing blood pressure drug may be able to prevent the molecular chain reaction in the brain triggered by ammonia.   

Hyperammonemia, or the toxic accumulation of ammonia in the blood, is a significant clinical problem.  Children with certain genetic metabolic disorders and people with impaired liver function because of chronic hepatitis, alcoholism, acetaminophen overdose, and other toxic liver conditions suffer from this condition.

Because ammonia is a gas, it can slip past the brain’s defenses.   When too much ammonia enters the brain, it overwhelms the brain’s normal waste removal process and tricks cells into firing in uncontrolled bursts, thereby triggering seizures which can lead to comas and even death. 

The study, which appears in the journal Nature Medicine, was lead by Maiken Nedergaard, M.D., D.M.Sc., the co-director of the URMC Center for Translational Neuromedicine.  

Using mouse models, the researchers observed that the ammonia mimicked the function of potassium resulting in two cellular malfunctions.  First, it caused nerve cells to become depolarized and therefore more likely to become excitable.  Second, it cause a key molecular gatekeeper – called NKCC1 – to go into overdrive and effectively suppress the nerve cells’ ability to stabilize itself after a spike in electrical activity. 

The researchers found that bumetanide, a diuretic drug used to treat high blood pressure, suppressed NKCC1 and controlled the seizures.   Because the drug is already approved for use, the threshold for moving into clinical studies is potentially lower, giving researchers a head start in efforts to develop a new treatment. 

You can read more about the study here.