A drug against high blood pressure promising for the treatment of Parkinson's disease and dementia in the context of a study in animals

A drug prescribed to treat high blood pressure has been shown to be promising against diseases such as Parkinson's disease, Huntington's disease and forms of dementia in studies in mice and mice. zebrafish at the University of Cambridge.

A common feature of these diseases – collectively referred to as neurodegenerative diseases – is the formation of misfolded proteins. These proteins, such as huntingtin in Huntington's disease and tau protein in certain dementias, form "aggregates" that can cause irreversible damage to nerve cells in the brain.

In healthy individuals, the body uses a mechanism to prevent the accumulation of these toxic substances. This mechanism is known as autophagy or "self-consumption" and implies that cells resembling "Pac-Man" eat and break down materials. However, in neurodegenerative diseases, this mechanism is impaired and unable to eliminate the proteins that accumulate in the brain.

As the world's population ages, more and more people are diagnosed with neurodegenerative disease, making the search for effective medicines even more urgent. However, there is currently no medication that can induce autophagy effectively in patients.

In addition to researching new drugs, scientists often seek to reuse existing drugs. These have the advantage of being safe for use in humans. If it is possible to demonstrate their effectiveness against target diseases, the shift to clinical use is much faster.

In a study published today in the journal Nature CommunicationsScientists at the UK Dementia Research Institute and the Cambridge Institute for Medical Research at the University of Cambridge have shown mice that felodipine, a medicine for hypertension, can be reused.

Epidemiological studies have already alluded to a possible link between the drug and the reduced risk of Parkinson's disease, but researchers have now shown that it can induce autophagy in several neurodegenerative states.

A team led by Professor David Rubinsztein used genetically modified mice to express mutations causing Huntington's disease or a form of Parkinson's disease, and zebrafish that model a form of dementia.

Mice are a useful model for studying human diseases because their short life span and fast reproductive speed make it possible to study biological processes in many fields. Their biology and physiology present a number of important features common to those of humans, including similar nervous systems.

Felodipine has been shown to be effective in reducing aggregation accumulation in mice with Huntington mutations and Parkinson's disease and in the zebrafish dementia model. Treated animals also had fewer signs of disease.

Studies in mice often use doses much higher than those known to be safe for humans. Professor Rubinsztein and colleagues showed in Parkinson's mice that it was possible to show beneficial effects even at concentrations similar to those tolerated by humans. They did it by controlling the concentrations with the help of a small pump placed under the skin of the mouse.

"It's the first time we realize that one study has shown that an approved drug can slow down the formation of harmful proteins in the brains of mice at doses aimed at mimicking the concentrations of this medicine in the man, "says Professor Rubinsztein. "As a result, the drug has been able to slow the progression of these potentially devastating conditions and so we believe that it should be tested in patients."

"This is only the first step, however.The drug will need to be tested on patients to see if it has the same effects in humans as in the mouse." We must be cautious, but I would like to say that we can be cautious optimism. "

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The study was funded by Wellcome, the Council of Medical Research, Alzheimer's Research UK, the Alzheimer Society, Rosetrees Trust, the Tau Consortium, an anonymous donation to the Parkinson's Center More Cambridge, Open Targets, the Science and Technology Program of Guangdong Province, with additional support from the Cambridge Biomedical Research Center of the National Institute of Health Research.

Reference

Siddiqi, FH et al. Felodipine induces autophagy in the brains of mice, with pharmacokinetics amenable to new use. Nature Communications; April 18, 2019; DOI: 10.1038 / s41467-019-09494-2

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