Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

"Bad" Enzymes May Wear White Hats After Stroke

29.03.2006
Enzymes that can harm the brain immediately after a stroke may actually be beneficial days later, according to new research. Insights from the study could change the way stroke is treated, extending the window for effective treatment from a couple of hours to a couple of weeks. The results may suggest new ideas for drug development.

Working with rats, a team from the Harvard Medical School Departments of Radiology and Neurology found that the enzyme matrix metalloproteinase-9 (MMP-9) may help remodel brain tissue seven to 14 days after a stroke. Their findings are published in the April 2006 issue of Nature Medicine, and were made available in an advance online publication on March 26, 2006.


MMP-9, stained green, with markers of neurovascular remodeling (in red).

Matrix metalloproteinases are a large group of enzymes that help break down the extracellular matrix, a complex structure that surrounds and supports cells. Newer research is showing that MMPs may also contribute to blood vessel growth, as well as the death, proliferation, differentiation, and movement of cells.

Sophia Wang, who was a Howard Hughes Medical Institute (HHMI) medical student fellow at Harvard Medical School, is second author of the article. She was deeply involved with the study’s data analysis, and established a way to quantify the response of proteins involved in the cell growth and blood vessel remodeling that occurs after stroke. She also assisted with behavioral studies of rats that had received MMPs to see how well they recovered after a stroke.

HHMI medical student fellows are medical students who are interested in biomedical research. The fellowships support a year of research, usually between the second and third years of medical school. The program is designed to encourage medical students to become physician-scientists.

Just after a stroke—a temporary loss of blood to the brain caused by a clot or burst blood vessel—MMPs chew up damaged brain tissue. This increases the risk of swelling and hemorrhage in the brain. Some current stroke treatment research seeks ways to inhibit MMPs to minimize their danger—but this new study shows that a different approach may be required in the long run.

"We have mostly thought of MMPs as being ’bad,’" said senior author Eng H. Lo of the Neuroprotection Research Laboratory at Massachusetts General Hospital, Wang’s mentor. "Our data strongly suggest that they play a totally different role during stroke recovery."

To understand the action of MMPs, the team induced stroke in rats and injected some with an MMP inhibitor at different times after the stroke. When the injection was given immediately following the stroke, rats showed smaller areas of brain damage. Injections given at three days had no effect, but those given at seven days or 14 days led to more extensive brain damage, compared with rats that did not receive an inhibitor.

The team also looked for MMPs within the brains of rats following stroke. They found the enzymes in the damaged areas at one and three days after the stroke. However, seven to 14 days after the stroke, high levels of MMPs were found instead in what’s known as the peri-infarct cortex—an area close to the damaged tissue that is involved in stroke recovery.

"The peri-infarct zone is very dynamic and potentially very malleable for long periods of time after stroke," said Lo. "I think that makes a big difference in how we think about treatment.

"One of the biggest problems facing stroke patients is that it’s a neurodegenerative disorder, but also a medical emergency," he explained. "With other neurological disorders, such as Alzheimer’s disease, the disease process is much slower. This study suggests that with stroke, we may now be able to think beyond acute treatment times of just a few hours, and find ways of manipulating peri-infarct recovery over several weeks."

Currently, the only FDA-approved drug for treating stroke—tissue plasminogen activator, or tPA—must be given within three hours after a stroke occurs. Otherwise, said Lo, the drug can amplify the "bad" effects of MMPs, increasing the risk of swelling and bleeding.

To further establish MMPs’ role in healing stroke damage, first author Bing-Qiao Zhao used two naturally occurring proteins as markers for neurovascular remodeling. He had the group look for Egr1 and RECA-1, both of which indicate neuron and blood vessel regrowth. Rats that received an MMP inhibitor seven days after stroke had much lower levels of these proteins, indicating impaired healing. These rats also had more problems completing a behavioral task than rats that did not receive an MMP inhibitor.

While current efforts to design MMP-targeted drugs aim to inhibit the enzymes completely after a stroke, the researchers caution that, based on their findings, it may be necessary to regulate the activity of MMPs much more precisely to enable the patient’s optimal recovery.

During nine months in Lo’s lab, Wang also conducted research involving MMPs, statins, and Alzheimer’s disease. Statins are a class of drugs that reduce serum cholesterol levels.

"I did some work suggesting that statins might counteract the hemorrhagic effect of tPA and might someday be used as an adjuvant therapy with tPA," she said. "I also did some work with beta amyloid, the protein implicated in Alzheimer’s disease. It seems that beta amyloid might increase levels of MMP-9 where MMPs would harm rather than help, and statins might help counteract that. So statins could play a role in treating Alzheimer’s disease."

Wang learned of Lo’s research during her undergraduate years at Harvard, where she earned a degree in biochemistry. Before choosing him as her mentor for the HHMI fellowship, she worked in his laboratory for a summer before matriculating at Mt. Sinai School of Medicine in New York. She’s scheduled to receive her M.D. in 2007.

"I was very fortunate to work on all these projects," Wang said. "I had a great time, and a wonderful mentor."

The first author on the Nature Medicine paper is Bing-Qiao Zhao, of the Neuroprotection Research Laboratory and Program in Neuroscience at Harvard. Authors Hahn-Young Kim, Hannah Storrie, Bruce R. Rosen, David J. Mooney, and Xiaoying Wang are also affiliated with Harvard.

Jennifer Donovan | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht 'Y' a protein unicorn might matter in glaucoma
23.10.2017 | Georgia Institute of Technology

nachricht Microfluidics probe 'cholesterol' of the oil industry
23.10.2017 | Rice University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Salmonella as a tumour medication

HZI researchers developed a bacterial strain that can be used in cancer therapy

Salmonellae are dangerous pathogens that enter the body via contaminated food and can cause severe infections. But these bacteria are also known to target...

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

3rd Symposium on Driving Simulation

23.10.2017 | Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

 
Latest News

Microfluidics probe 'cholesterol' of the oil industry

23.10.2017 | Life Sciences

Gamma rays will reach beyond the limits of light

23.10.2017 | Physics and Astronomy

The end of pneumonia? New vaccine offers hope

23.10.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>