Nanoparticles with traditional Chinese medicine to cure Parkinson’s disease

Disease and treatment 18. nov 2020 3 min Professor Daniel E. Otzen, Postdoc Hossein Mohammad-Beigi Written by Morten Busch

Parkinson’s disease develops because the cell membrane in the brain’s dopamine-producing cells is destroyed by a small naturally occurring protein – alpha-synuclein. The process can be prevented by baicalein, a traditional Chinese medicine. To get the medicine to and into the cells, researchers have developed nanoscale particles called nanoliposomes that can cross the blood–brain barrier and the membranes of brain cells, where they can protect against the destructive attacks.

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The development of many drugs has been thwarted by the inability to find a practical delivery mechanism to deliver the drug through the body to the intended target. Baicalein is a small molecule that prevents the small, unstable protein alpha-synuclein from misfolding and accumulating in clusters and clumps that destroy brain cells and can lead to Parkinson’s disease. Unfortunately, baicalein is unstable and difficult to dissolve and is therefore difficult to use as medicine, but new research has changed this.

“Nanoparticles have proven useful for increasing the stability, solubility and availability of drugs. Our recent study shows that encapsulating baicalein into nanoliposomes can solve these problems. The drug thereby appears to be able to cross the blood–brain barrier effectively and counteract the destructive effects of alpha-synuclein among people with Parkinson's disease,” explains Daniel E. Otzen, Professor, Interdisciplinary Nanoscience Center (iNANO) and Department of Molecular Biology and Genetics, Aarhus University.

Nanoscale drug-delivery capsules

People with Parkinson’s disease lose neurons in the grey matter in the midbrain. About 1% of the people older than 65 years have Parkinson’s, which is caused by an imbalance in the brain resulting from alpha-synuclein, a small unstable protein that accumulates in clusters and clumps. Previously it was thought that the clustering and clumping to form insoluble fibrils is the main problem, but today it is thought that smaller soluble aggregates of the protein, called oligomers, are the most toxic.

“The problem arises at the interface between two fluid phases – the oligomers of alpha-synuclein and the cell membrane. Evidence suggests that the oligomers create disorder in the cell membrane and, as it turns out, promote the uncontrolled transport of small metal ions across the membrane barrier. Fortunately, this undesirable interaction can be suppressed or completely eliminated,” explains co-author Farhang Aliakbari, who has been a visiting scientist at iNANO, Aarhus University and has done much of the current work at the National Institute of Genetic Engineering and Biotechnology in Tehran, Iran, co-supervised by Dina Morshedi.

Baicalein, a flavonoid derived from the traditional Chinese medicinal plant Scutellaria baicalensis Georgi, appears to be capable of doing that. It can stop Parkinson’s disease from developing by generally reducing oxidative stress and inflammation in the brain, inhibiting the clumping of alpha-synuclein and stimulating defective neurons to die and new ones to form.

“The clusters of alpha-synuclein interact with many proteins in the cell and thereby create many problems for people with Parkinson’s disease. They destroy both the cell’s outer membranes and the internal organelles such as the mitochondria. Baicalein can almost eliminate these problems if it can be delivered into the cells, which has been the greatest challenge,” says Farhang Aliakbari.

By combining dipalmitoylphosphatidylcholine (DPPC) lipids, cholesterol and the water-soluble polymer PEG2000, the researchers incorporated baicalein into liposomes (nanoscale drug-delivery capsules). This enabled the otherwise water-repellent substance to be transported through the blood plasma and across the blood–brain barrier and cellular membrane.

“The nanoscale liposomes have three roles. They ensure that an otherwise very reactive hydrophobic small molecule can be securely transported and effectively cross barriers, and the liposomes make baicalein even more potent than usual by enhancing its ability to prevent the formation of alpha-synuclein aggregations,” explains co-author Hossein Mohammad-Beigi, Postdoctoral Fellow, iNANO, Aarhus University.

Slowing the disease

The new research demonstrates the enormous potential of nanoliposomes for treating people with neurogenerative diseases such as Parkinson’s and similar diseases. As part of the study, the group also carried out research on mice exposed to Parkinson’s disease via the pesticide rotenone and showed that baicalein is neuroprotective in animals. This highlights how nanoliposomes’ ability to mobilize poorly soluble drugs can have important advantages for people with Parkinson’s disease.

“The fact that the nanoliposomes are biocompatible with body fluids, are biodegradable and can contain and transport both hydrophobic and hydrophilic drugs makes them extremely suitable for transporting baicalein and many other drugs since they treat both the chemical structure and reduce side effects elsewhere in the body, and we can design them to release the drug when the nanoliposomes reach the target,” says Daniel E. Otzen.

The steady ageing of populations highlights a growing need for therapeutic approaches to neurodegenerative diseases, and although these are increasing, no effective treatment is currently in sight – only therapies that reduce clinical symptoms.

“Current therapies can only reduce and alleviate symptoms. Dopamine analogues can reduce the clinical symptoms of Parkinson’s disease but do not prevent the disease from progressing and showing side effects. Conversely, the new treatment can disrupt the protein clusters’ capacity to destroy the membrane, so that we can slow down and perhaps even reverse the disease,” concludes Daniel E. Otzen.

Multiple Protective Roles of Nanoliposome‐Incorporated Baicalein against Alpha‐Synuclein Aggregates” is published in Advanced Functional Materials. “A triple role for a bilayer: using nanoliposomes to cross and protect cellular membranes” is being considered for publication by the Journal of Membrane Biology. In 2017, the Novo Nordisk Foundation awarded a grant to Daniel E. Otzen for the project Specific Binders Crossing the Blood–brain Barrier to Diagnose and Combat Parkinson’s Disease.

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