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Health Care, Healthcare, Public Health, Science, Uncategorized

Could A Heart Failure Drug Change The Way We Treat ALS?

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New research from the Washington University School of Medicine in St. Louis, MO, suggests a medication used to treat heart failure could be adapted to treat amyotrophic lateral sclerosis – also known as Lou Gehrig’s Disease.

Amyotrophic lateral sclerosis (ALS), which has been in the spotlight recently with the now famous Ice Bucket Challenge, is a fatal neurodegenerative disease with no known cure. It causes the deterioration of specific nerve cells in the brain and spinal cord called motor neurons, which control muscle movement. As the illness progresses, patients lose their ability to walk, talk and breathe, eventually leading to death.

According to the ALS Association, around 5,600 people in the US are diagnosed with ALS each year. Disease incidence is 2 in 100,000 people, and as many as 30,000 Americans may have ALS at any given time. The organization notes that the life expectancy of an average ALS patient is between 2-5 years from diagnosis, though many people live with quality for 5 years or more.

Unfortunately, the only FDA-approved drug to treat the disease, called riluzole, has shown only “marginal benefits” in patients. But now, scientists may have discovered an entirely new approach to treating the devastating illness.

The team behind the new study, published in the journal Nature Neuroscience, studied how, when they reduced the activity of an enzyme or limited cells’ ability to make enzyme copies, ALS’ destruction of nerve cells ceased.

They explain that the enzyme maintains balance of sodium and potassium in cells, but they blocked the enzyme with digoxin – a drug used to treat congestive heart failure and slow heart rate in patients with atrial fibrillation.

“This had a very strong effect,” explains senior author Dr. Azad Bonni, “preventing the death of nerve cells that are normally killed in a cell culture model of ALS.”

Astrocytes play key role in neurodegenerative disorders

To conduct their research, Dr. Bonni and colleagues studied brain cell stress responses in a mouse model of ALS. The mice had a mutated version of a gene that causes an inherited form of the disease, the team explains, which causes them to develop many symptoms seen in humans with ALS.

When they were monitoring the activity of a stress response protein in the mice, the researchers unexpectedly came across another enzyme – called sodium-potassium ATPase – which expels sodium particles from cells and pulls in charged potassium particles, enabling cells to keep an electrical charge across their outer membranes.

The researchers explain that maintaining this charge is vital for normal cell function. The specific sodium-potassium ATPase from the team’s research is found in nervous system cells known as astrocytes. However, in the ALS mice, levels of the enzyme are higher than what is found in normal astrocytes.

Results of their study revealed that the increase in sodium-potassium ATPase prompted the astrocytes to release inflammatory cytokines, which may kill motor neurons.

In previous studies, it has been suggested that astrocytes play a key role in neurodegenerative disorders – including ALS, Alzheimer’s, Huntington’s and Parkinson’s diseases.

Dr. Bonni explains that placing astrocytes from ALS mice in culture dishes with healthy motor neurons causes them to degenerate and die, adding that “even though the neurons are normal, there’s something going on in the astrocytes that is harming the neurons.

Motor nerve cells survived when enzyme blocked with digoxin

But the mechanism behind why the astrocytes harm the neurons is unclear. The research team’s findings, however, suggest the sodium-potassium ATPase is a critical component.

When the team blocked the enzyme in ALS astrocytes by using digoxin, they found that the motor nerve cells survived. They explain that digoxin blocks the ability of sodium-potassium ATPase to expel sodium and take in potassium.

Of the mice with the mutation for inherited ALS, those that had only one copy of the gene for sodium-potassium ATPase survived around 20 days longer, compared with the mice with two copies of the gene.

“The mice with only one copy of the sodium-potassium ATPase gene live longer and are more mobile,” says Dr. Bonni. “They’re not normal, but they can walk around and have more motor neurons in their spinal cords.”

According to the team, cells make less of the enzyme when one copy of the gene is gone.

Though the findings offer a starting point for further studies, Dr. Bonni notes that there are still important questions to be answered about how sodium-potassium ATPase enzyme inhibitors could be used to slow progressive paralysis in ALS.

 

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