World War II Chemical Weapon Antidote May Also Fight Parkinson’s, Researchers Suggest

dimercaprol for Parkinson's

Dimercaprol, an antidote to a World War II chemical weapon, was shown to be effective in removing a neurotoxin associated with Parkinson’s, revealing it as a possible treatment for the neurodegenerative disease.

Purdue University researchers report that the antidote can safely and effectively remove acrolein, a neurotoxic substance, from the body. Earlier this year, the researchers from the laboratory of professor Riyi Shi, MD, PhD, published their results on the chemical warfare antidote as a potential Parkinson’s treatment in the Journal of Neurochemistry.

Acrolein is a neurotoxin generated in the body after nerve cells are damaged and is directly linked to Parkinson’s disease. Exposure to acrolein increases pain and triggers a cascade of biochemical events thought to increase the severity of Parkinson’s and other neurodegenerative diseases.

The researchers administered dimercaprol to rats with increased levels of acrolein and nerve damage, a model applicable to Parkinson’s disease, and tested the ability of dimercaprol to block acrolein and neurodegenerative disease progression.

They observed that dimercaprol neutralized acrolein and eliminated it from the brain. Importantly, adding dimercaprol led to an increased survival rate of neurons, improved mobility, and less pain. They also demonstrated that dimercaprol could effectively neutralize acrolein in human cells.

Dimercaprol has several advantages over other chemicals that isolate and eliminate acrolein, including fewer side effects and being easily processed by the body and eliminated via the urine.

“Our studies show that by removing the toxin (acrolein) from the brain, we are not just reducing the symptoms of Parkinson’s disease but also significantly reversing the damage of Parkinson’s disease. This could actually provide a new treatment for Parkinson’s patients,” said Shi, a professor of neuroscience and biomedical engineering in Purdue’s Department of Basic Medical Sciences, College of Veterinary Medicine, and Weldon School of Biomedical Engineering.

Dimercaprol is already approved by the U.S. Food and Drug Administration to treat heavy metal poisoning, so it is known to be safe when administered to humans. Future clinical trials are necessary to test the effectiveness of dimercaprol as a treatment for patients with Parkinson’s and other neurodegenerative diseases.

“We believe that the drug’s classification and method of administration are what make it an attractive therapy option,” Shi said. “By systematically injecting the antidote drug directly into the abdominal cavity, it can be absorbed by the bloodstream and then travel to the brain, where the disease is most harmful and where the drug can most benefit the patient.”

The research was funded by grants from the National Institutes of Health, the Indiana State Department of Health, and the Indiana CTSI Collaboration in Biomedical Translational Research Pilot Program.

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Researchers Receive Funding to Study New Gene Linked to Parkinson’s Disease

gene linked to Parkinson's

A multidisciplinary research team at Purdue University in Indiana and the University of Bordeaux in France was awarded a $107,000 grant by the The Michael J. Fox Foundation for Parkinson’s Research to study the neuroprotective ability of a newly discovered gene associated with Parkinson’s disease.

The gene was discovered by Jean-Christophe Rochet, PhD, a professor of medicinal chemistry and molecular pharmacology at Purdue, when he and Min Zhang, PhD, a professor of statistics at Purdue, identified a list of genes related to Parkinson’s by analyzing several data sets obtained from one of the National Institutes of Health-Designated Data Repositories.

“While some of the genes on the list were already known, Chris [Rochet] found an interesting gene that has not been reported to be directly associated with Parkinson’s disease yet,” Zhang said in a press release.

The gene, called NFE2L1, produces a protein that controls other genes involved in the survival and maturation of dopaminergic neurons.

Parkinson’s disease is caused by the impairment or death of these dopamine-producing nerve cells, or neurons, in a region of the brain called the substantia nigra, which controls the body’s balance and movement.

“NFE2L1 levels are reduced in dopaminergic neurons in the brains of Parkinson’s disease patients,” Rochet said. “We recently found in a large-scale genomic study that a minor allele of NFE2L1 can lower Parkinson’s risk. These observations imply that neuron death in Parkinson’s disease may result in part from a loss of the neuroprotective action of NFE2L1.”

Researchers hypothesize that increasing the production of the NFE2L1 protein in rodent models of Parkinson’s disease will reduce nerve cell death.

The team then intends to screen for compounds that can increase NF2L1 levels in the brain, either by stimulating its production or by blocking its degradation by the proteasome, a protein complex that destroys unnecessary or damaged proteins.

This research will not only shed light on the protein’s ability to reduce neurotoxicity, but the team also hopes it will aid in the development of Parkinson’s therapies that target NFE2L1 levels in the brain.

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Molecule from Fat Burning Linked to Protein Clumps That Typify Parkinson’s in Study

acrolein and protein clumps

A molecule created by the brain burning fat for fuel can accumulate in some people and turn toxic, playing a key role in their possibly developing Parkinson’s disease,  researchers at Purdue University report.

These findings, in the study “Acrolein-mediated neuronal cell death and alpha-synuclein aggregation: implications for Parkinson’s Disease” published in Molecular and Cellular Neurosciencecould also aid in earlier disease diagnosis and new treatment discoveries.

The researchers found that acrolein, a byproduct of burning fat — which brain uses as fuel — that  is normally eliminated from the body can promote the accumulation of alpha-synuclein. This buildup, in turn, leads to nerve cell death in the substantia nigra, a brain area crucial for movement control. Damage to nerve cells in this region linked to clumping of the alpha-synuclein protein is a hallmark of Parkinson’s disease.

Using a rat model of Parkinson’s, the team observed that acrolein levels were unusually high in these rats and toxic, leading to  alpha-synuclein clumps in their brains.

Importantly, they also found a molecule that in these animals addressed both the toxic protein accumulation and the disease symptoms linked to it.

“Acrolein is a novel therapeutic target, so this is the first time it’s been shown in an animal model that if you lower the acrolein level you can actually slow the progression of the disease,” Riyi Shi, PhD, the study’s senior author, said in a Purdue news article written by Steve Tally. “This is very exciting. We’ve been working on this for more than 10 years.”

Early promise an animal model, however, may or may not lead to discoveries that help patients. “In decades of research, we’ve found many ways to cure Parkinson’s disease in pre-clinical animal studies, and yet we still don’t have a disease therapy that stops the underlying neurodegeneration in human patients,” said Jean-Christophe Rochet, PhD, a study co-author.

Still, “it’s possible that a drug therapy could be developed based on this information,” Rochet added. “We’ve shown that acrolein isn’t just serving as a bystander in Parkinson’s disease. It’s playing a direct role in the death of neurons.”

The investigators found that hydralazine, a molecule that widens blood vessels and lowers blood pressure  — and is an approved blood pressure treatment, eased behavioral problems in these rats, as well as in healthy rats injected with the compound.

Hydralazine, which scavenges acrolein, was also able to lessen neuronal death and lower levels of rotenone, another Parkinson’s-related toxin. “Luckily, this is a compound that can bind to the acrolein and remove it from the body,” Shi said. “It’s a drug already approved for use in humans, so we know there is no toxicity issue.”

Hydralazine may not be the best choice for Parkinson’s patients, however, due to its effects on blood pressure. But “we may find there is a therapeutic window, a lower dose, that could work without leading to unwanted side-effects,” Rochet said. “Regardless, this drug serves as a proof of principle for us to find other drugs that work as a scavenger for acrolein.”

In fact, the team has already “identified multiple candidates” that might “lower acrolein with similar or greater effectiveness, but without lowering blood pressure,” Rochet added.

This discovery might also allow earlier disease detection, Shi said, as acrolein levels “can be detected easily, such as using urine or blood,” meaning its levels could serve as a biomarker.

“The goal is that in the near future we can detect this toxin years before the onset of symptoms and initiate therapy to push back the disease … [maybe] indefinitely. That’s our theory and goal,” Shi added.

Rochet previously worked with a research team in Norway that showed that salbutamol, a common asthma medicine, could lower Parkinson’s risk by half, according to a University of Bergen 2017 report.

“Evidence suggests that salbutamol acts by a different mechanism than hydralazine — that is, by reducing alpha-synuclein accumulation — and thus perhaps salbutamol and an acrolein-scavenging drug could be used together to achieve an even greater therapeutic effect,” Rochet hypothesized.

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NIH awards $228,325 to Tech Startup to Develop MRI Device for Improved Diagnosis

MRI scan device

A startup developing a device for more affordable and efficient magnetic resonance imaging (MRI) scans was recently awarded a Small Business Technology Transfer (STTR) grant from the National Institutes of Health.

MR-Link, a technology company affiliated with Purdue University, will receive $228,325 to develop the device. Researchers say it will provide better imaging and promises to improve the diagnosis of Parkinson’s disease and other imaging-diagnosed diseases, while lowering costs and reducing health risks.

“This grant is validation for us that our idea is on the right track and there is a need for these kind of technologies that may help researchers to understand human physiology more accurately,” Ranajay Mandal, one of three MR-Link co-founders and a graduate student at Purdue University’s Weldon School of Biomedical Engineering, said in a press release.

Designed to be inserted into an existing MRI machine, the coin-sized device is synchronized with the MRI system to perform multiple scans at once, allowing researchers to record, stimulate, and image the brain and other organs. By incorporating electro-physiological signals from several organs, the new device promises to more effectively provide insight on a patient’s physiology.

STTR is a highly competitive program that awards federal funding to small businesses and nonprofit institutions to support scientific and technological innovation, and increase private sector commercialization of these innovations.

Out of more than 1,000 applications received from startups throughout the U.S. for Phase 1 STTR grants, only 169 were funded. MR-Link is the only one to receive funding from the state of Indiana, out of 32 that applied.

“We will use this funding to further develop our device and software into a user-friendly system, so that MR-Link can begin to distribute its beta testing units to MRI researchers,” said co-founder Nishant Babaria, a graduate student at the Purdue School of Electrical and Computer Engineering. “We hope to also use the money to enrich our research team with new professionals to help us package the software and hardware.”

MR-Link is reaching out to research facilities first before moving into the clinical market.

“We are open to partnerships with other laboratories and device manufacturers so we could soon deliver devices to more people and to benefit their research and to hopefully soon deliver to clinicians for them to better treat patients,” said co-founder Zhongming Liu, PhD, an assistant professor of electrical and computer engineering and biomedical engineering at Purdue.

The researchers are presenting the device at the upcoming International Society for Magnetic Resonance in Medicine, June 16-21, 2018, in Paris.

MR-Link is opening offices in the Purdue Research Park in West Lafayette, Indiana, the largest university-affiliated business incubation complex in the country.

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