Nature | Hypertension Drug Felodipine Shows Promise in Treating Parkinson’s and Alzheimer’s Diseases

Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, have long been formidable challenges that scientists strive to overcome. In particular, Alzheimer’s disease has attracted substantial annual investments of effort and funding from both the scientific community and pharmaceutical companies; however, significant breakthroughs remain elusive. Although new research findings are frequently reported, a definitive therapeutic victory has yet to emerge.

Researchers are not only seeking treatments for these diseases through new drugs, but also continuously exploring breakthroughs among existing medications. A research team at the University of Cambridge, led by Professor David Rubinsztein, a professor of neurogenetics, has demonstrated that prescription drugs used to treat hypertension show promise as candidate therapies for human Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

In healthy individuals, the body employs a mechanism to prevent the accumulation of such toxic substances, known as autophagy. Autophagy is a major intracellular pathway for cytoplasmic protein degradation, mediated by double-membrane structures that engulf portions of the cytoplasm and cellular components requiring degradation, such as organelles and proteins, to form autophagosomes. These autophagosomes ultimately fuse with lysosomes, where their contents are degraded to meet the cell’s metabolic needs and facilitate the renewal of certain organelles.

Most neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, are characterized by the accumulation of large amounts of toxic proteins within the cytoplasm of neurons. These proteins, such as mutant huntingtin (HD), α-synuclein (Parkinson’s), and Tau protein (in various dementias), cause irreversible damage to nerve cells in the brain.

Studies in mice have demonstrated that felodipine can prevent the accumulation of toxic proteins in animal models of neurodegenerative diseases by promoting autophagy, a cellular process that clears abnormal and unnecessary proteins. Importantly, the drug can cross the blood-brain barrier to reach affected neurons and is effective at doses acceptable for humans.

The scientists’ findings were described in a paper titled “Felodipine Induces Autophagy in the Mouse Brain” as follows: “Our data indicate that felodipine induces autophagy in neurons and enhances the clearance of a range of pathogenic proteins, such as huntingtin protein associated with Huntington’s disease, α-synuclein linked to Parkinson’s disease, and Tau protein related to Alzheimer’s disease.”

The authors also wrote in their paper published in Nature Communications: “This is the first time we have recognized that an already marketed drug can slow the accumulation of harmful proteins in the brains of mice. Moreover, the dosage used in the trials is similar to the concentration tolerated by humans. The drug can slow the progression of these potentially devastating diseases, so we believe it can be tested in humans.”

The authors explain that neurodegenerative diseases are typically characterized by aggregates or clumps of specific proteins within the neuronal cytoplasm, such as huntingtin in Huntington’s disease, α-synuclein in Parkinson’s disease, and tau protein associated with various forms of dementia. Cells naturally employ autophagy to engulf and degrade unwanted or abnormal proteins. Furthermore, studies in animal models have demonstrated that enhancing autophagy through pharmacological or genetic means can promote the clearance of protein aggregates and ameliorate these neurodegenerative conditions.

Rubinsztein’s team has screened existing drugs approved for other indications to identify those that may also enhance autophagy, thereby potentially aiding in the treatment of neurodegenerative diseases by promoting the clearance of abnormal protein aggregates. However, as the authors point out, although many candidates capable of inducing autophagy have been identified, the doses used in mice may be far higher than those tolerable in humans. “Thus, any effects observed with such compounds in mice may not be achievable in humans, because the required drug concentrations far exceed those acceptable in humans. This situation renders these drugs unsuitable for direct repurposing.”

A research team at the University of Cambridge previously discovered that verapamil, a calcium channel blocker used to treat hypertension (specifically an L-type calcium channel blocker), effectively induces autophagy. They further confirmed using multiple tools that L-type calcium channels are mTOR-independent targets of autophagy. Verapamil can clear α-synuclein, which is implicated in Parkinson’s disease, and reduce huntingtin protein levels in Drosophila and zebrafish models of Huntington’s disease. However, verapamil does not cross the blood-brain barrier, making it unsuitable as a candidate drug for treating neurodegenerative diseases in humans.

In their latest study, the team screened other calcium channel blockers in the same class as verapamil and identified felodipine as a potential candidate capable of crossing the blood-brain barrier. Previous epidemiological studies had suggested a possible link between felodipine and a reduced risk of Parkinson’s disease in patients with hypertension, but the team’s recent research in zebrafish and mouse models has confirmed that this drug may be a clinically relevant option for treating neurodegenerative diseases.

Felodipine effectively reduced the accumulation of huntingtin protein in zebrafish and mouse models of Huntington’s disease, and also alleviated disease symptoms in the mouse models. To investigate whether autophagy could be induced in the mouse brain at steady-state concentrations, scientists used miniaturized pumps implanted under the animals’ skin to control drug administration. Encouragingly, in a mouse model of Huntington’s disease, administration of felodipine at human-equivalent doses led to a significant reduction in huntingtin protein aggregates and decreased the accumulation of α-synuclein in the brains of Parkinson’s disease mouse models.

UK regulations permit the use of micro-pumps in mice only during specified time periods, thereby preventing the team from evaluating human-relevant felodipine concentrations in mouse models of other neurodegenerative diseases that require longer durations to manifest. The authors also stated, “This is currently just the first phase. The drug still needs to be tested in humans to determine whether it produces the same effects in people as it does in mice. We need to be cautious, but I would say we can also be cautiously optimistic.”

References:

https://www.nature.com/articles/s41467-019-09494-2

https://www.genengnews.com/news/hypertension-drug-shows-promise-against-multiple-neurodegenerative-diseases/