Reduced levels of an important neurotransmitter found in multiple sclerosis patients

ScienceDaily (Feb. 11, 2011) — Researchers at the University of Illinois at Chicago have shown for the first time that damage to a particular area of the brain and a consequent reduction in noradrenaline are associated with multiple sclerosis.

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The study is available online in the journal Brain.

The pathological processes in MS are not well understood, but an important contributor to its progression is the infiltration of white blood cells involved in immune defense through the blood-brain barrier.

Douglas Feinstein, research professor in anesthesiology at the UIC College of Medicine, and his colleagues previously showed that the neurotransmitter noradrenaline plays an important role as an immunosuppressant in the brain, preventing inflammation and stress to neurons. Noradrenaline is also known to help to preserve the integrity of the blood-brain barrier.

Because the major source of noradrenaline is neurons in an area of the brain called the locus coeruleus, the UIC researchers hypothesized that damage to the LC was responsible for lowered levels of noradrenaline in the brains of MS patients.

"There's a lot of evidence of damage to the LC in Alzheimer's and Parkinson's disease, but this is the first time that it has been demonstrated that there is stress involved to the neurons in the LC of MS patients, and that there is a reduction in brain noradrenaline levels," said Paul Polak, research specialist in the health sciences in anesthesiology and first author on the paper.

For the last 15 years, Feinstein and his colleagues have been studying the importance of noradrenaline to inflammatory processes in the brain.

"We have all the models for studying this problem, so in some ways it was a small step to look at this question in MS," said Polak.

The researchers found that LC damage and reduced levels of noradrenaline occur in a mouse model of MS and that similar changes could be found in the brains of MS patients.

The findings suggest that LC damage, accompanied by reduction in noradrenaline levels in the brain, may be a common feature of neurologic diseases, Polak said.

"There are a number of FDA-approved drugs that have been shown to raise levels of noradrenaline in the brain, and we believe that this type of therapeutic intervention could benefit patients with MS and other neurodegenerative diseases, and should be investigated," he said.

Sergey Kalinin, post-doctoral research associate in anesthesiology, also contributed to the study. This study was supported by grants from the Department of Veteran Affairs and Partners for Cures.

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High iron, copper levels block brain-cell DNA repair

ScienceDaily (May 20, 2011) — No one knows the cause of most cases of Alzheimer's, Parkinson's and other neurodegenerative disorders. But researchers have found that certain factors are consistently associated with these debilitating conditions. One is DNA damage by reactive oxygen species, highly destructive molecules usually formed as a byproduct of cellular respiration. Another is the presence of excessive levels of copper and iron in regions of the brain associated with the particular disorder.

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University of Texas Medical Branch at Galveston researchers have discovered how these two pieces of the neurodegenerative disease puzzle fit together, a connection they describe in a review article in the current Journal of Alzheimer's Disease. A high level of copper or iron, they say, can function as a "double whammy" in the brain by both helping generate large numbers of the DNA-attacking reactive oxygen species and interfering with the machinery of DNA repair that prevents the deleterious consequences of genome damage.

"It's been suggested that an imbalance of DNA damage and repair produces a buildup of unrepaired genetic damage that can initiate neurodegenerative pathology," said postdoctoral fellow Muralidhar Hegde, lead author of the paper. "We don't yet know enough about all the biochemical mechanisms involved, but we have found multiple toxic mechanisms linking elevated iron and copper levels in the brain and extensive DNA damage -- pathological features associated with most neurodegenerative disorders."

Humans ordinarily have small amounts of iron and copper in their bodies -- in fact, the elements are essential to health. But some people's tissues contain much larger quantities of iron or copper, which overwhelm the proteins that normally bind the metals and sequester them for safe storage. The result: so-called "free" iron or copper ions, circulating in the blood and able to initiate chemical reactions that produce reactive oxygen species.

"Reactive oxygen species cause the majority of the brain cell DNA damage that we see in Alzheimer's and Parkinson's disease, as well as most other neurodegenerative disorders," Hegde said. "It's bad enough if this damage occurs on one strand of the DNA double helix, but if both strands are damaged at locations close to each other you could have a double-strand break, which would be fatal to the cell."

Normally, special DNA repair enzymes would quickly mend the injury, restoring the genome's integrity. But experiments conducted by Hegde and his colleagues showed that iron and copper significantly interfere with the activity of two DNA repair enzymes, known as NEIL1 and NEIL2.

"Our results show that by inhibiting NEIL1 and NEIL2, iron and copper play an important role in the accumulation of DNA damage in neurodegenerative diseases," Hegde said.

The researchers got a surprise when they tested substances that bond to iron and copper and could protect NEIL1 from the metals. One of the strongest protective agents was the common South Asian spice curcumin, which also has been shown to have other beneficial health effects.

"The results from curcumin were quite beautiful, actually," Hegde said. "It was very effective in maintaining NEIL activity in cells exposed to both copper and iron."

Other authors of the Journal of Alzheimer's Disease paper include research associate Pavana Hegde; K.S. Rao, director of the Institute for Scientific Research and High Technology Services in Panama; and UTMB Professor Sankar Mitra. The United States Public Health Service and the American Parkinson's Disease Association supported this research.

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