For release: Thursday, August 3, 2006
In a surprise twist, researchers have learned that a type of enzyme that contributes to brain damage immediately after a stroke also plays a role in brain remodeling and movement of neurons days after stroke. Understanding the secondary role for this enzyme in healing stroke damage may lead to new treatments for stroke and offer a longer window of time for treatment.
Previous studies have shown that enzymes called matrix metalloproteinases (MMPs) contribute to stroke damage by chewing up and degrading the supporting material between the cells, called the cellular matrix. This can result in bleeding or cell death. Now, Eng Lo, Ph.D., and colleagues from the departments of radiology and neurology at Massachusetts General Hospital and the Harvard Medical School show that, days after a stroke, one of the MMPs, called MMP-9, moves into the stroke-affected area and helps repair damaged tissue. This new finding suggests that MMP-9 may be a double agent, meaning the same enzyme may cause good or bad results in the brain.
The study results were reported in The Journal of Neuroscience* and Nature Medicine.** Both studies were funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).
MMP-9 is an enzyme which naturally exists in the brain. Currently tPA (tissue Plasminogen Activator), the only FDA-approved treatment for stroke, must be used within 3 hours of the onset of symptoms. While tPA helps to dissolve clots in blood vessels that cause strokes, it also increases levels of MMP-9, which can cause bleeding complications. MMP inhibitors seem to supplement the positive effects of tPA, and this has prompted researchers to propose that these drugs would be good candidates for stroke treatment. However, Dr. Lo’s research shows that inhibition of MMPs during the later time period after stroke actually hinders brain repair and may paradoxically increase the risk of bleeding in the brain.
“We need to think about the role of MMP-9 in stroke and its treatments as having two phases – an acute phase, which is damage producing, and a later phase, which helps with repair,” says Dr. Lo. “Treatments that affect MMP-9 will have different consequences depending on when they are given.”
“Early on in the developing brain, MMPs have a role to play in structuring and modeling. We have assumed that this beneficial role didn’t reoccur in the mature brain. However, we now know that the brain’s plasticity allows this initial remodeling to happen again,” says Dr. Lo.
Both studies used rodent models of stroke to examine the role of MMP-9 after brain injury. After stroke, neuroblasts (cells from which nerve tissue is formed) swerve away from their designated path and move towards damaged areas. This cellular migration requires help from special enzymes. The Journal of Neuroscience study shows that the migration of these cells through the tangle of damaged brain tissue uses MMPs. Researchers injected markers into the mouse brain to monitor the movement of the cells and examined their final location 14 days after the stroke. MMP-9 co-localized with these markers of neuroblast migration, and inhibiting MMP stopped the movement of these neurons to the damaged site. This is the first study to show that MMPs are required for neuroblast migration as the brain attempts to heal itself.
In the Nature Medicine study, Dr. Lo and his colleagues examined the action of MMPs with respect to timing after stroke damage. In rats, an MMP inhibitor was administered at different times after an induced stroke. When the injection was given immediately following the stroke, rats showed smaller areas of brain damage. Injections given at 3 days had no effect, while blocking MMPs at 7 days or 14 days led to more extensive brain damage in the treated rats. These findings highlight the time-dependent nature of MMP activity. Delayed inhibition of MMPs after a stroke seems to have negative effects, while early inhibition of MMPs may help protect the brain.
The scientists also examined the role MMPs play in remodeling within the brains of rats following stroke. Researchers located the enzymes in the damaged areas of the brain at 1 and 3 days after the stroke. However, 7 to 14 days after the stroke, high levels of MMPs were found instead in the region surrounding the initial damage, called the peri-infarct cortex. The peri-infarct cortex is the location where newly born immature neurons migrate and where axons sprout new connections after a stroke. The reorganization in the peri-infarct area is correlated with functional recovery after stroke. The increased presence of MMPs in this area suggests that it has a beneficial role in remodeling after brain injury.
“We need to think carefully about the use of MMP inhibitors after stroke and about their possible effects. Our current research shows that the brain is actively trying to heal itself after stroke,” says Dr. Lo. “This dynamic state of remodeling in the brain signals us to not give up hope after the initial stroke event and to recognize that the therapeutic window may be longer than we assumed.”
Previous studies have shown that MMPs contribute to blood vessel growth, as well as proliferation, differentiation and movement of cells. These diverse and important functions may explain the paradoxical positive and negative effects of MMPs. Future studies in Dr. Lo’s lab will examine the effects of low-dose and slow-release treatments with MMP-9 and MMP inhibitors. Dr. Lo hypothesizes that to achieve the biggest impact on stroke therapies, scientists must take into account the timing and specific brain area placement of MMP activity.
“It is a powerful lesson to learn that the same molecule can do very different things. Learning how to manipulate the system will be the key to developing improved treatments,” say Dr. Lo. “Combination therapy using tPA and short-term inhibitor MMPs would be invaluable for targeting acute treatment, while some way of modulating MMPs or controlling neurovascular proteolysis days later may provide a new approach for post-stroke therapy and could extend the narrow treatment time that we currently race against.”
The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
*Lee S-R, Kim H-Y, Rogowska J, Zhao B-Q, Bhide P, Parent JM, and Lo EH. “Involvement of Matrix Metalloproteinase in Neuroblast Cell Migration from the Subventricular Zone after Stroke.” The Journal of Neuroscience, March 29, 2006, Vol. 26, pp. 3491-3495.
**Zhao B-Q, Wang S, Kim H-Y, Storrie H, Rosen BR, Mooney DJ, Wang X, and Lo, EH. “Role of Matrix Mettaloproteinases in Delayed Cortical Responses after Stroke.” Nature Medicine, April 2006, Vol. 12, pp. 441-445.
-By Michelle D. Jones-London, Ph.D.
Last Modified September 15, 2008