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 How molecules teeter in a laser field
18.01.2019 | Forschungsverbund Berlin

nachricht Discovery of enhanced bone growth could lead to new treatments for osteoporosis
18.01.2019 | University of California - Los Angeles

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Ten-year anniversary of the Neumayer Station III

The scientific and political community alike stress the importance of German Antarctic research

Joint Press Release from the BMBF and AWI

The Antarctic is a frigid continent south of the Antarctic Circle, where researchers are the only inhabitants. Despite the hostile conditions, here the Alfred...

Im Focus: Ultra ultrasound to transform new tech

World first experiments on sensor that may revolutionise everything from medical devices to unmanned vehicles

The new sensor - capable of detecting vibrations of living cells - may revolutionise everything from medical devices to unmanned vehicles.

Im Focus: Flying Optical Cats for Quantum Communication

Dead and alive at the same time? Researchers at the Max Planck Institute of Quantum Optics have implemented Erwin Schrödinger’s paradoxical gedanken experiment employing an entangled atom-light state.

In 1935 Erwin Schrödinger formulated a thought experiment designed to capture the paradoxical nature of quantum physics. The crucial element of this gedanken...

Im Focus: Nanocellulose for novel implants: Ears from the 3D-printer

Cellulose obtained from wood has amazing material properties. Empa researchers are now equipping the biodegradable material with additional functionalities to produce implants for cartilage diseases using 3D printing.

It all starts with an ear. Empa researcher Michael Hausmann removes the object shaped like a human ear from the 3D printer and explains:

Im Focus: Elucidating the Atomic Mechanism of Superlubricity

The phenomenon of so-called superlubricity is known, but so far the explanation at the atomic level has been missing: for example, how does extremely low friction occur in bearings? Researchers from the Fraunhofer Institutes IWM and IWS jointly deciphered a universal mechanism of superlubricity for certain diamond-like carbon layers in combination with organic lubricants. Based on this knowledge, it is now possible to formulate design rules for supra lubricating layer-lubricant combinations. The results are presented in an article in Nature Communications, volume 10.

One of the most important prerequisites for sustainable and environmentally friendly mobility is minimizing friction. Research and industry have been dedicated...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Our digital society in 2040

16.01.2019 | Event News

11th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Aachen, 3-4 April 2019

14.01.2019 | Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

 
Latest News

Additive manufacturing reflects fundamental metallurgical principles to create materials

18.01.2019 | Materials Sciences

How molecules teeter in a laser field

18.01.2019 | Life Sciences

The cytoskeleton of neurons has been found to be involved in Alzheimer's disease

18.01.2019 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>