New research finds that acrolein, a byproduct of oxidative stress, is key in the progression of Parkinson's disease. Targeting the compound was found to slow down the condition in rats — a discovery that may soon lead to new drugs for the illness.
The condition is neurodegenerative, meaning that the neurons in a brain area tied to motor skills and movement control gradually deteriorate and die.
These brain cells would normally produce dopamine, which is a neurotransmitter key for regulating complex movements as well as controlling mood.
Although current therapies for Parkinson's involve drugs such as Levodopa, which the brain can use to create dopamine, the reason why dopaminergic neurons die in the first place remains unknown.
So, now, a team of researchers led by two professors at Purdue University in West Lafayette, IN, investigated the hypothesis that a product of oxidative stress might be a key player in this cell death and the development of the disease.
Oxidative stress takes place when oxygen radicals are produced in excess, a process that results in a series of damaging effects, such as increased toxicity and damage to our DNA.
Riyi Shi and Jean-Christophe Rochet, who are both professors at the Purdue Institute for Integrative Neuroscience and the Purdue Institute for Drug Discovery, jointly led the research, whose results were published in the journal Molecular and Cellular Neuroscience.
Studying acrolein in rats
Profs. Shi, Rochet, and colleagues used a model of genetically modified rats to induce Parkinson's-like symptoms and study the behavior of their dopaminergic cells, both in vitro and in vivo.
The researchers found that the compound called acrolein tends to build up in the brain tissue of rats affected by Parkinson's.
Acrolein, as the researchers explain, is a toxic byproduct of the brain burning fat for energy. The compound is normally discarded from the body.
Interestingly, however, the study revealed that acrolein raises the levels of alpha-synuclein. This is the clumpy protein that is believed to kill dopamine-producing neurons because it accumulates in unusual amounts in the brain cells of those with Parkinson's or Lewy body dementia.
Additionally, injecting acrolein into healthy rats produced behavioral deficits typical of Parkinson's. So, next, the researchers wanted to see if targeting this compound would stop the disease from progressing.
Blocking acrolein slows down Parkinson's
To this end, the team conducted experiments both in cell cultures and in the animals, evaluating their anatomy and the functionality of their behavior.
Remarkably, the scientists found that inhibiting acrolein with hydralazine alleviated Parkinson's-like symptoms in rats, as the study's co-lead author reports.
"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 [...]."
Prof. Riyi Shi
"This is very exciting," he says. "We've been working on this for more than 10 years."
"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," adds Prof. Rochet.
Rats vs. humans: Toward new drugs
Prof. Rochet cautions that, although promising, finding a drug that halts the disease in rats is still a far cry from finding an equivalent compound in humans.
"In decades of research, we've found many ways to cure Parkinson's disease in preclinical animal studies," he says, "and yet we still don't have a disease therapy that stops the underlying neurodegeneration in human patients."
"But this discovery gets us further down the drug discovery pipeline, and it's possible that a drug therapy could be developed based on this information," Prof. Rochet adds.
Although hydralazine is already in use and we know that it has no noxious effects, the researchers say that it may not prove to be the best anti-Parkinson's drug down the line, for various reasons.
"Regardless," Prof. Rochet continues, "this drug serves as a proof of principle for us to find other drugs that work as a scavenger for acrolein."
"It is for this very reason," Prof. Shi explains, that "we are actively searching for additional drugs that can either more efficiently lower acrolein, or do so with fewer side effects."
"The key is to have a biomarker for acrolein accumulation that can be detected easily, such as using urine or blood," he says.
"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. We might be able to delay the onset of this disease indefinitely. That's our theory and goal."
Prof. Riyi Shi