Substance in Humans is Effective Fighting Stroke Damage

A molecular substance that occurs naturally in humans and rats was found to “substantially reduce” brain damage after an acute stroke and contribute to a better recovery, according to a newly released animal study by researchers at Henry Ford Hospital.

The study, published online before print in Stroke, the journal of the American Heart Association, was the first ever to show that the peptide AcSDKP provides neurological protection when administered one to four hours after the onset of an ischemic stroke.

This type of stroke occurs when an artery to the brain is blocked by a blood clot, cutting off oxygen and killing brain tissue with crippling or fatal results.

“Stroke is a leading cause of death and disability worldwide,” said Li Zhang, M.D., a researcher at Henry Ford and lead author of the study. “Our data showed that treatment of acute stroke with AcSDKP alone or in combination with tPA substantially reduced neurovascular damage and improved neurological outcome.”

Commonly called a “clot-buster,” tPA, or tissue plasminogen activator, is the only FDA-approved treatment for acute stroke.

However, tPA must be given shortly after the onset of stroke to provide the best results. It also has the potential to cause a brain hemorrhage.

The Henry Ford study found that this narrow “therapeutic window” is extended for up to four hours after stroke and the therapeutic benefit of tPA is amplified when tPA is combined with AcSDKP. Further, the researchers discovered that AcSDKP alone is an effective treatment if given up to one hour after the brain attack.

The researchers tested the actions of both substances on laboratory rats in which acute stroke had been induced. It was already known that the peptide AcSDKP provides anti-inflammatory effects and helps protect the heart when used to treat a variety of cardiovascular diseases. The Henry Ford scientists reasoned that the peptide may have similar neurological benefits.

Significantly, they found that AcSDKP can readily cross the so-called “blood brain barrier” that blocks other neuroprotective substances.

A battery of behavioral tests was given to the lab rats both before and after stroke was induced to measure the effects of AcSDKP administered alone one hour after onset and combined with tPA four hours after stroke.

Besides finding that both methods “robustly” decreased neurological damage associated with stroke, they did so without increasing the incidence of brain hemorrhage or the formation of additional blood clots.

“With the increased use of clot-busting therapy in patients with acute stroke, both the safety and effectiveness of the combined treatment shown in our study should encourage the development of clinical trials of AcSDKP with tPA,” Dr. Zhang says.

Experimental drug reduces brain damage in rodents

An experimental drug called 3K3A-APC appears to reduce brain damage, eliminate brain hemorrhaging and improve motor skills in older stroke-afflicted mice and stroke-afflicted rats with comorbid conditions such as hypertension, according to a new study from Keck Medicine of USC.

The report, which appears online in the journal Stroke, provides additional evidence that 3K3A-APC may be used as a therapy for stroke in humans, either alone or in combination with the Food and Drug Administration (FDA)-approved clot-busting drug therapy known as tissue plasminogen activator (tPA). Clinical trials to test the drug’s efficacy in people experiencing acute ischemic stroke are expected to begin recruiting patients across the United States next year.

“Currently, tPA is the best treatment for stroke caused by a blocked artery, but it must be administered within three hours after stroke onset to be effective,” said Berislav Zlokovic, director of the Zilkha Neurogenetic Institute (ZNI) at the Keck School of Medicine of USC and the study’s lead investigator. “Because of this limited window, only a small fraction of those who suffer a stroke reach the hospital in time to be considered for tPA. Our studies show that 3K3A-APC extends tPA’s therapeutic window and counteracts tPA’s tendency to induce bleeding in the brains of animals having a stroke.”

Zlokovic is the scientific founder of ZZ Biotech, a Houston-based biotechnology company he co-founded with USC benefactor Selim Zilkha to develop biological treatments for stroke and other neurological ailments.

ZZ Biotech’s 3K3A-APC is a genetically engineered variant of the naturally occurring activated protein C (APC), which plays a role in the regulation of blood clotting and inflammation. 3K3A-APC has been shown to have a protective effect on the lining of blood vessels in rodent brains, which appears to help prevent bleeding caused by tPA.

In collaboration with Cedars-Sinai Medical Center and The Scripps Research Institute, Zlokovic and his team gave tPA — alone and in combination with 3K3A-APC — to mature female mice and male hypertensive rats four hours after stroke. They also gave 3K3A-APC in regular intervals up to seven days after stroke. The researchers measured the amount of brain damage, bleeding and motor ability of the rodents up to four weeks after stroke.

The researchers found that, under those conditions, tPA therapy alone caused bleeding in the brain and did not reduce brain damage or improve motor ability when compared to the control. The combination of tPA and 3K3A-APC, however, reduced brain damage by more than half, eliminated tPA-induced bleeding and significantly improved motor ability.

“Scientists all around the globe are studying potential stroke therapies, but very few have the robust preclinical data package that 3K3A-APC has,” said Kent Pryor, ZZ Biotech’s chief operating officer. “The results from Dr. Zlokovic’s studies have been very promising.”

Zlokovic’s team previously reported similar results in young, healthy male rodents. A Phase 1 trial testing the safety of 3K3A-APC in healthy human volunteers, led by study co-author Patrick D. Lyden of Cedars-Sinai concluded in February.

“We now have opened an investigational new drug application at the FDA to conduct a Phase 2 clinical trial of 3K3A-APC in patients experiencing acute ischemic stroke,” said Joe Romano, CEO and president of ZZ Biotech. “We are excited to see 3K3A-APC move from healthy volunteers to real patients suffering from this terrible disease.”

Averting the Devastating Effects of Stroke

Researchers at the University of Connecticut Health Center are studying ways to prevent the devastating injuries to the body caused by stroke, a leading cause of serious long-term disability.

One American dies from stroke, sometimes called a “brain attack,” every four minutes. More than five times that many people survive a stroke, and for them, the physical damage it causes can be enormous.

“Stroke often doesn’t kill you, but some patients say they would have rather died than be left with severe disability and not be able to care for themselves,” says Dr. Louise D. McCullough, professor of neurology and neuroscience and director of stroke research. “People can often be disabled from their stroke. They need assistance with feeding and sometimes can’t get out of bed. Many can’t speak or communicate, and this is very isolating. And now we’re seeing an increasing number of stroke survivors as our population ages.”

There are two types of stroke. Ischemic strokes, which account for the vast majority, happen when clots block the blood vessels to the brain and cut off blood flow. Hemorrhagic strokes happen when the wall of a blood vessel breaks and blood leaks into the surrounding brain. Signs of either type of stroke include sudden numbness or weakness of the face or arm or leg, especially on one side of the body, as well as sudden confusion, difficulty speaking or understanding, trouble seeing or walking, dizziness or loss of balance, and/or a sudden severe headache.

McCullough’s research focuses on ischemic stroke. This type of stroke can be treated in an emergency room with “clot-busting” medication called tissue plasminogen activator (tPA), which helps reduce damage to the brain. But tPA can be effective only if given within a few hours of a stroke, and many people don’t immediately realize they are having a stroke and don’t seek help right away. In addition, some people can’t receive tPA because of other health issues.

“Nationwide, only 5 to 8 percent of people who have a stroke get tPA effectively,” she says. “So we’ve been limited in treatment. We’ve never been able to find a drug to protect the brain after stroke. Reperfusion (restoring the blood flow using tPA) is less useful because the brain is already damaged.”

So McCullough’s research involves studying factors such as what contributes to brain injury after a stroke and how it might be reversed. Because women tend to do worse than men in terms of survival and disability, she also is studying the role that hormones play in stroke risk and recovery.

Much of the understanding about stroke and its treatment has stemmed from research in men, but not all of those findings can benefit women, she points out. “Stroke is different in women – how we present, how we respond to drugs, how we recover. Women have a higher risk of stroke, a slower recovery and more cognitive problems. We need to understand the sex differences on a cellular level. For example, cell death occurs by different pathways in the two sexes. We’re trying to figure out why the biology is different and whether that’s important to therapy.”

In addition, women and men respond differently to different types of drugs. McCullough points to basic aspirin as an example of this. In women, a daily dose of aspirin can help prevent stroke but seems to have no impact in preventing heart disease. In men, the opposite is true.

Interestingly, McCullough also has found a correlation between social factors and stroke. In a study funded by the National Institutes of Health (NIH), McCullough is using mouse models to understand the role that social isolation might play in ischemic stroke.

“We’ve found that isolation is as big a risk factor for having a stroke as hypertension (high blood pressure),” she explains. “We also found that if we induce a stroke in a mouse that is isolated from others, the stroke is 40 percent bigger. And three days after a stroke, a mouse that is placed with others does better than a mouse that is alone. So now we’re saying that with hospitalized patients, maybe we should put someone who has had a stroke in a room with, say, someone who has had a hip replacement.”

McCullough earned her medical degree and Ph.D. from UConn’s School of Medicine. She completed an internship, residency and fellowship at Johns Hopkins University in Baltimore before returning to Connecticut after her father, a physicist, suffered a disabling stroke. She hopes her research will help people like her father as well as future generations, including her four children ranging in age from 7 to 13, whose framed artwork covers larger portions of the walls in her office than do the smaller certificates honoring her with Best Doctor awards and Outstanding Teacher recognition.

In a nearby office, Dr. Lauren Hachmann Sansing, assistant professor of neurology, is looking at stroke in another way. Her research focuses on hemorrhagic stroke, the type that results from a ruptured blood vessel in the brain. “This type of stroke is devastating,” she explains. “It affects two million patients a year, and only 50 percent survive it. People may become paralyzed, unable to speak and unconscious due to the mass of blood within the brain.”

This intracerebral bleeding induces an immune reaction in the body in which white blood cells (leukocytes) travel to the brain in response to the injury. Unfortunately, this does further harm by causing brain swelling and actually worsens the cell death caused by the stroke. Sansing has obtained an NIH K08 grant – funds awarded to support the research of new physician-scientists – to study how this immune reaction can be prevented.

“Using a mouse model, we are measuring and quantifying how many leukocytes travel to the brain and how we could block them using certain anti-inflammatory drugs, such as arthritis drugs that target this cell population,” Sansing says. “We are working to determine which pathways are active in patients after a stroke, and we think we are onto something. We’re using drugs already tested in humans, with good safety data, and so we already know the dosing. If we find efficacy in animal models, we can go right to safety in human studies.”

Working to understand and treat this secondary wave of injury after a stroke is an interesting mix of the neurology and immunology courses that Sansing enjoyed as a student. She completed undergraduate studies at Cornell University, her medical degree at SUNY Stony Brook School of Medicine, and a master’s in translational research (which involves converting scientific discovery into health improvement) at the University of Pennsylvania, where she also completed an internship, residency and fellowships in vascular neurology and translational medicine.

“We’re hopeful about our work,” Sansing says. “But there have been many, many treatments for stroke that have worked in animal models but failed to improve outcomes in patients. With the evolution of biomarkers studies and the ability to study proteins and activation in patients, we have a lot of insights into what we should go after as potential targets. Dr. McCullough and I have a large biobank of samples from stroke patients who have donated blood samples to help us study the disease. These samples help ensure that what we study in our animal models is important in our patients.”

Both McCullough and Sansing are involved in active research while also seeing patients, and they say their studies are greatly benefitted by doing both. “It’s like a big puzzle,” Sansing explains. “We create a model, study it, go back to patients, then go back to research. Our overall goal is to someday say we have a new treatment that can make a difference in people’s lives.”