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Dr. Okun

Post of the Week: The Role of Inflammation in Parkinson's Disease

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Dr. Okun    409

Dear Forum members,

 

There has been a lot of research focused on a potential role for inflammation in PD and also a role for anti-inflammatories (NSAIDS like ibuprofen) in modifying risk of PD. Here is an interesting basic science study from Scripps this week on the topic.

 

 

Scripps Research Institute Team Identifies a Potential Cause of Parkinson’s Disease that May Lead to New Treatment Options

 

LA JOLLA, CA – November 19, 2012 – Deciphering what causes the brain cell degeneration of Parkinson’s disease has remained a perplexing challenge for scientists. But a team led by scientists from The Scripps Research Institute (TSRI) has pinpointed a key factor controlling damage to brain cells in a mouse model of Parkinson’s disease. The discovery could lead to new targets for Parkinson’s that may be useful in preventing the actual condition.

The team, led by TSRI neuroscientist Bruno Conti, describes the work in a paper published online ahead of print on November 19, 2012 by theJournal of Immunology.

Parkinson’s disease plagues about one percent of people over 60 years old, as well as some younger patients. The disease is characterized by the loss of dopamine-producing neurons primarily in the substantia nigra pars compacta, a region of the brain regulating movements and coordination.

Among the known causes of Parkinson’s disease are several genes and some toxins. However, the majority of Parkinson’s disease cases remain of unknown origin, leading researchers to believe the disease may result from a combination of genetics and environmental factors.

Neuroinflammation and its mediators have recently been proposed to contribute to neuronal loss in Parkinson’s, but how these factors could preferentially damage dopaminergic neurons has remained unclear until now.

Making Connections

Conti and his team were looking for biological pathways that could connect the immune system’s inflammatory response to the damage seen in dopaminergic neurons. After searching human genomics databases, the team’s attention was caught by a gene encoding a protein known as interleukin-13 receptor alpha 1 chain (IL-13Ra1), as it is located in the PARK12 locus, which has been linked to Parkinson’s.

IL-13ra1 is a receptor chain mediating the action of interleukin 13 (IL-13) and interleukin 4 (IL-4), two cytokines investigated for their role as mediators of allergic reactions and for their anti-inflammatory action.

With further study, the researchers made the startling discovery that in the mouse brain, IL-13Ra1 is found only on the surface of dopaminergic neurons. “This was a ‘Wow!’ moment,” said Brad Morrison, then a TSRI postdoctoral fellow and now at University of California, San Diego, who was first author of the paper with Cecilia Marcondes, a neuroimmunologist at TSRI.

Conti agrees: “I thought that these were very interesting coincidences. So we set out to see if we could find any biological significance.”

The scientists did—but not in the way they were expecting.

‘Something New Going On’

The scientists set up long-term experiments using a mouse model in which chronic peripheral inflammation causes both neuroinflammation and loss of dopaminergic neurons similar to that seen in Parkinson’s disease. The team looked at mice having or lacking IL-13Ra1 and then compared the number of dopaminergic neurons in the brain region of interest.

The researchers expected that knocking out the IL-13 receptor would increase inflammation and cause neuronal loss to get even worse. Instead, neurons got better.

“We were very surprised at first,” said Conti. “When we stopped to think, we got very excited because we understood that there was something new going on.”

Given that cells fared better without the receptor, the team next explored whether damage occurred when dopaminergic neurons that express IL-13Ra1 were exposed to IL-13 or IL-4. But exposure to IL-13 or IL-4 alone did not induce damage.

However, when the scientists exposed the neurons to oxidative compounds, they found that both IL-13 and IL-4 greatly enhanced the cytotoxic effects of oxidative stress.

“This finally helps us understand a basic mechanism of the increased susceptibility and preferential loss of dopaminergic neurons to oxidative stress associated with neuroinflammation,” said Marcondes.

The finding also demonstrated that anti-inflammatory cytokines could contribute to neuronal loss. In their article, the authors note they are not suggesting that inflammation is benign but that IL-13 and IL-4 may be harmful to neurons expressing the IL-13Ra1, despite their ability to ultimately reduce inflammation. “One could say that it is not the fall that hurts you, but how you stop,” said Conti.

More Clues

Along with these results, additional clues suggest that the IL-13 receptor system could be a major player in Parkinson’s. For instance, some studies show Parkinson’s as more prevalent in males, and the gene for IL-13Ra1 is located on the X chromosome, where genetic variants are more likely to affect males.

And, though not definitive, other studies have suggested that Parkinson’s disease might be more common among allergy sufferers. Since IL-13 plays a role in controlling allergic inflammation, Conti wonders if the IL-13 receptor system might explain this correlation.

If further research confirms the IL-13 receptor acts in a similar way in human dopaminergic neurons as in mice, the discovery could pave the way to addressing the underlying cause of Parkinson’s disease. Researchers might, for instance, find that drugs that block IL-13 receptors are useful in preventing loss of dopaminergic cells during neuroinflammation. And, since the IL-13 receptor forms a complex with the IL-4 receptor alpha, this might also be a target of interest. With much exciting research ahead, Conti said, “This is just the beginning.”

This research was funded by the Ellison Medical Foundation; National Institutes of Health grants AG028040 and DA030908; and the Ministry of Education, Culture, Sports, Science and Technology of Japan.

In addition to Morrison, Marcondes and Conti, the other authors on the paper, “IL-13Ra1 expression in dopaminergic neurons contributes to their oxidative stress-mediated loss following chronic systemic treatment with LPS,” were Daniel Nomura, Manuel Sanchez-Alavez, Alejandro Sanchez-Gonzalez, Indrek Saar, and Tamas Bartfai, from TSRI, Kwang-Soo Kim from Harvard University, Pamela Maher from the Salk Research Institute, and Shuei Sugama from the Nippon Medical School in Tokyo.

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amphibians    0

I read that NSAID has positive effect in treating neuroinflammation but its long term use is not recommended. The extract from perwinkle flower called vinpocetine can be used for long term treatment of anti neuroinflammation. Do you have information on this?

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Dr. Okun    409

There is no recommendation supporting the use of NSAIDS for the treatment of PD at this time.

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MusicMan    769

For what it's worth, I have been on Ibuprofen for 3 years or so for my bad back. It would certainly be nice if there has been some added benefit to taking all of it. In any event, I was wondering if I was okay still taking the advil/hydrocodone while I'm on PD meds.

Interestingly, as stated in the study, I'm also an allergy sufferer and was on immunotherapy (shots) for years. Just another risk factor....

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Dr. Okun    409

In general Advil is a dose not detrimental to the kidney/stomach and regulated by the doc is ok.  In general and if possible we try our best to avoid opiates which can make some PD symptoms worse and worsen constipation.  This is not always possible.  They are usually safe when monitored.

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DaveN    425

Dr, Okun,

 

Can you expand on which symptoms can be made worse by opiates?  I'm aware of the constipation issue already.

 

Thanks.

 

Dave

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Dr. Okun    409

We worry the most about cognition and the development of confusion with opiates and Parkinson.

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MusicMan    769

We worry the most about cognition and the development of confusion with opiates and Parkinson.

I take very little hydrocodone, just as needed for my back when it is acting up (disc issues). But is this confusion and cognition issue PERMANENT, or just while you are ON the medication? In other words, is it lasting damage to the brain, or a side effect of the medicine while it is in your system?

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