A University of Cambridge-led research team has shown how a prescription drug that is used to treat high blood pressure may represent a promising candidate for treating disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease in humans. The researchers’ studies in mice demonstrated that the drug, felodipine can prevent the build-up of toxic proteins in animal models of neurodegenerative diseases, by boosting a process known as autophagy, by which cells clear abnormal and unwanted proteins. Importantly, the drug was effective at doses normally seen in humans, and could cross the blood-brain barrier to reach the affected neurons.
“Our data suggest that felodipine induces autophagy in neurons and enhances removal of a range of disease-causing proteins: mutant huntingtin, mutant α-synuclein, and tau,” the authors wrote in their paper, published today in Nature Communications. “This is the first time that we’re aware of that a study has shown that an approved drug can slow the build-up of harmful proteins in the brains of mice using doses aiming to mimic the concentrations of the drug seen in humans,” commented David Rubinsztein, PhD, professor of molecular neurogenetics at the department of medical genetics and UK Dementia Research Institute, Cambridge Institute for Medical Research, University of Cambridge. “As a result, the drug was able to slow down the progression of these potentially devastating conditions and so we believe it should be trialed in patients.” The scientists’ findings are described in a paper titled, “Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing.”
Neurodegenerative diseases commonly feature clumps, or aggregates of specific proteins in the cytoplasm of neurons, the authors explained. Such proteins include mutant huntingtin in Huntington’s disease, α-synuclein in Parkinson’s disease, and tau in various forms of dementia. Cells naturally employ the process of autophagy to engulf and degrade unwanted or abnormal proteins, and tests in animal models have shown that boosting autophagy through the use of drugs or genetic approaches can enhance the clearance of protein aggregates and improve signs of such neurodegenerative disease.
Rubinsztein’s team and others have sifted through existing drugs that are approved for other indications, to find those that may also increase autophagy, and so which could feasibly help to treat neurodegenerative diseases by boosting the clearance of abnormal protein clumps. However, as the authors pointed out, while a number of autophagy-inducing candidates have been identified, animal studies using these repurposed drugs haven’t tested whether they would be effective against neurodegenerative diseases at the doses used for their original indication. This issue is “critical,” they noted, as doses reached in mice may be much higher than those seen in humans. “Thus, it is possible that the effects of any such compounds seen in mice may not be achievable in humans, as the benefits may be due to on-target or off-target drug effects at concentrations much higher than those seen in humans,” the investigators stated. “This scenario would make the drugs unsuitable for direct repurposing.”
The University of Cambridge team had previously found that the calcium channel blocker, verapamil, which is used to treat high blood pressure, effectively induced autophagy, and could enhance the clearance of abnormal Parkinson’s disease-causing α-synuclein in cultured cells, as well as reduce mutant huntingtin toxicity in Drosophila and zebrafish models of Huntington’s disease. However, verapamil doesn’t cross the blood-brain barrier, and so wouldn’t be a workable candidate as a treatment for human neurodegenerative diseases.
In their latest studies, the team screened other calcium channel blockers in the same class as verapamil, and identified felodipine as a potential candidate that does cross the blood-brain barrier. While prior epidemiological studies have hinted at a possible link between felodipine and reduced risk of Parkinson’s disease in hypertensive patients, the team’s latest studies in zebarafish and mouse models have now confirmed that the drug may represent a clinically relevant option for treating neurodegenerative disorders.
Initial studies reported in Nature Communications confirmed that felodipine effectively reduced the build up of toxic huntingtin protein in zebrafish and mouse models of Huntington’s disease, and also reduced signs of the disease in a mouse model. For these mouse studies the drug was administered intraperitoneally, and concentrations were higher than those typically reached in humans. To investigate whether autophagy could be induced in the mouse brain at steady-state concentrations that were more similar to those typically seen humans, drug administration was controlled using drug delivery minipumps implanted under the animals’ skin. Encouragingly, administration of human-equivalent doses of felodipine led to significant reductions in huntingtin protein aggregation in one mouse model of Huntington’s disease, and reduced the build up of insoluble mutant α-synuclein in the brains of a mouse model of Parkinson’s disease. The treated Parkinson’s disease animals also demonstrated improved grip strength compared with control animals.
U.K. regulations only permit the use of minipumps for a defined period of time, so the team wasn’t able to evaluate human-relevant concentrations of felodipine in mouse models of other neurodegenerative disorders that take longer to manifest. Nevertheless, the authors stated, “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 … we believe that this is the first study showing that an approved drug at concentrations similar to those seen in human patients can induce autophagy in rodent brains, as well as the first study showing that an approved drug under such conditions can ameliorate neurodegenerative disease in a mouse model … These data support testing in humans with appropriate neurodegenerative diseases.”
Commenting on the newly published studies, Rubinsztein acknowledged that the results in animals represent “only the first stage … The drug will need to be tested in patients to see if it has the same effects in humans as it does in mice,” he commented. “We need to be cautious, but I would like to say we can be cautiously optimistic.”