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Cholesterol drug STATIN side-effects under research
University of Arizona, a research team working on neurons treated with statin has made a new discovery; unusual ball-like swellings within neurons, which the team has termed the "beads-on-a-string" effect. The team is not yet entirely sure why the beads form. However, the team believes that further investigation of the beads will help inform why some people experience cognitive declines while taking statins, a wide-spread class of cholesterol reducing drugs.

"What we think we've found is a laboratory demonstration of a problem in the neuron that is a more severe version for what is happening in some peoples' brains when they take statins," said Restifo, a UA professor of neuroscience, neurology and cellular and molecular medicine, and principal investigator on the project.

Restifo and her team's co-authored study and findings were published in Disease Models & Mechanisms. Robert Kraft, a former research associate in the department of neuroscience, is lead author on the article. Restifo and Kraft cite data collected from clinical studies of patients, which refers to patients being told by their physicians that the negative cognitive effects experienced after taking statins are age-related symptoms. However, the research teams new findings imply that the neurodegenerative effects experienced by the patients are a result of the neurons negative reaction to statin.

After concluding that the likely culprit for this is statin, the team found that removing statins results in a disappearance of the beads-on-a-string, and also a restoration of normal neural growth. In further research the UA team intends to investigate how genetics may be involved in the bead formation to determine how hypersensitivity to the drugs can occur in some people. Team members believe that genetic differences could involve neurons directly, or the statin interaction with the blood-brain barrier.

"This is a great first step on the road toward more personalized medication and therapy. If we can figure out a way to identify patients who will have certain side effects, we can improve therapeutic outcomes." said David M. Labiner, who heads the UA department of neurology.

The research team has many external fundings and grants pending, and they hope to further their research to inform the doctors and patients of potential hazards and complications using this drug.

"If we are able to do genetic studies, the goal will be to come up with a predictive test so that a patient with high cholesterol could be tested first to determine whether they have sensitivity to statins," Restifo said.
Restifo uses an analogy with traffic to illustrate her teams findings.
The beads represent a sort of traffic jam, she described. In the presence of statins, neurons undergo a "dramatic change in their morphology,"
"Those very, very dramatic and obvious swellings are inside the neurons and act like a traffic pileup that is so bad that it disrupts the function of the neurons," she said.

Kraft's observations led to team's novel discovery. Restifo, Kraft and their colleagues had long been investigating mutations in genes, largely for the benefit of advancing discoveries toward the improved treatment of autism and other cognitive disorders. A stumbling led them to take another direction in their research, focusing on the apparent effect of statin.

The team tested over a thousand blind-selected drug components on fruit fly neurons, testing for possible mutating effects. Then Kraft observed that one compound, then another and then two more all created the same reaction "these bulges, which we called beads-on-a-string,'" Kraft said. "And they were the only drugs causing this effect."

"There is no question that these are very important and very useful drugs," Restifo said. Statins are used worldwide to lower cholesterol and prevent blood clots, heart attacks and strokes. But too much remains unknown about how the drugs' effects may contribute to muscular, cognitive and behavioral changes.

"We don't know the implications of the beads, but we have a number of hypotheses to test," Restifo said, hoping that further research by her team will help to better understand what exactly happens when the transportation systems in neurons are compromised.

"If statins have an effect on how the nervous system matures, that could be devastating. Memory loss or any sort of disruption of your memory and cognition can have quite severe effects and negative consequences.” Kraft said.

R. Kraft, A. Kahn, J. L. Medina-Franco, M. L. Orlowski, C. Baynes, F. Lopez-Vallejo, K. Barnard, G. M. Maggiora, L. L. Restifo. A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions. Disease Models & Mechanisms, 2012;
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