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!
Atomic-level motion may drive bacteria's ability to evade immune system defenses
24.04.2017 | Indiana University
Two-dimensional melting of hard spheres experimentally unravelled after 60 years
24.04.2017 | University of Oxford
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
24.04.2017 | Physics and Astronomy
24.04.2017 | Materials Sciences
24.04.2017 | Life Sciences