Can a blood pressure drug protect the brain from Parkinson's?
24 April, 2019
A prescription drug already in use for the treatment of high blood pressure could be effective against conditions such as Parkinson's, Alzheimer's, and Huntington's, in which toxic proteins build up in brain cells.
Scientists at the University of Cambridge in the United Kingdom and the Guangzhou Institutes of Biomedicine and Health in China suggest that the hypertension drug felodipine could be a promising candidate for "repurposing" as a treatment for neurodegenerative conditions.
In experiments with zebrafish and mice, they showed that felodipine can prompt a cellular recycling process called autophagy to clear away toxic proteins in brain cells, or neurons.
"Our data suggest," they write in a recent Nature Communications paper, "that felodipine induces autophagy in neurons and enhances removal of a range of disease-causing proteins: mutant huntingtin, mutant [alpha]-synuclein, and tau."
Mutant huntingtin is characteristic of Huntington's disease, while mutant alpha-synuclein and tau are hallmarks of Parkinson's disease and Alzheimer's disease, respectively.
The study is important because it shows that felodipine can remove mutant alpha-synuclein from the brains of mice at blood levels "similar to those that would be seen in humans taking the drug [for hypertension]."
"This is the first time," says corresponding study author David C. Rubinsztein, a professor of molecular neurogenetics at the University of Cambridge, "that we're aware of that a study has shown that an approved drug can slow the buildup of harmful proteins in the brains of mice using doses aiming to mimic the concentrations of the drug seen in humans."
"As a result," he continues, "the drug was able to slow down progression of these potentially devastating conditions and so we believe it should be trialed in patients."
Toxic proteins and autophagy
The production of proteins in cells is complex and involves many components. The process makes a long chain of amino acids and then folds it into a 3D shape.
However, when proteins do not fold correctly, they can accumulate into potentially toxic clusters. Such accumulation is a trigger for autophagy, a cell function that removes the faulty proteins, breaks them down, and recycles the components.
Prof. Rubinsztein and his colleagues comment that neurodegenerative diseases such as Parkinson's, Huntington's, and Alzheimer's commonly feature the "accumulation of aggregate-prone proteins within [...] neurons," and they cite studies that have shown how impairing autophagy can lead to such accumulation.
Studies have also shown that inducing autophagy chemically or genetically in flies, zebrafish, and mice can clear away these toxic proteins and reduce the damage they cause.
However, as yet, there are no treatments for neurodegenerative diseases that use "autophagy inducers." One way to develop treatments would be start from scratch with new experimental drugs.
Another way would be to search for potential candidates among the drugs that regulators have already approved for other human conditions and test them for the new condition. Such a route can cut the time and cost of developing a new treatment.
Grounds for 'cautious optimism'
The scientists used genetically altered mice and zebrafish for their study. The mice had gene alterations that induced them to develop either Huntington's disease or a type of Parkinson's disease. The zebrafish had gene alterations that induced changes that model a form of dementia.
Treatment with felodipine reduced the buildup of toxic, incorrectly folded proteins and signs of disease in the mouse models of Huntington's disease and Parkinson's disease, as well as in the zebrafish model of dementia.
When scientists study the effects of drugs in mice, they typically use higher levels than the doses that are safe in humans. In this study, however, the team showed that the blood levels of felodipine necessary for triggering autophagy were similar to those in humans.
They inserted "minipumps" under the mice's skin to enable drug concentrations at levels similar to those of humans and to keep the levels steady without wild fluctuations.
"Our data with this minipump administration suggest that at human-like plasma concentrations, felodipine can induce autophagy in the brains of mice and clear aggregate-prone disease-causing proteins," conclude the study authors.
These results are just the beginning, says Prof. Rubinsztein. "We need to be cautious," he adds, "but I would like to say we can be cautiously optimistic."
"The drug will need to be tested in patients to see if it has the same effects in humans as it does in mice."
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