ATLANTA – An old intravenous antibiotic may have new life as a stroke treatment, researchers say.
Minocycline appears to reduce stroke damage in multiple ways – inhibiting white blood cells and enzymes that, at least acutely, can destroy brain tissue and blood vessels, respectively, says Dr. David Hess, chair of the Department of Neurology in the Medical College of Georgia School of Medicine.
The broad-spectrum antibiotic also seems to reduce cell suicide in the minutes and hours following a stroke, enabling more cells to recover.
He and other researchers leading a clinical trial that will study the drug in 60 stroke patients in Georgia, Kentucky and Oregon say they believe the antibiotic will be a safe, effective adjunct therapy for tPA, the only FDA-approved drug therapy for strokes.
“It’s a safe drug that is easy to give and tolerate, that gets into the brain well, and may reduce bleeding, the primary side effect of tPA,” says Dr. Hess, principal investigator on the $1.8 million National Institute of Neurological Disorders and Stroke-funded clinical trial.
“We think it will make strokes smaller and patient outcomes better.”
Their animal studies have shown the drug, given within six hours of a stroke, then every 12 hours for up to three days – the peak time of inflammation – reduces stroke damage by up to 40 percent.
“We know it’s safe in humans and we know the concentrations we need to see improvement in the brains of rats can be achieved safely in humans,” says Dr. Susan C. Fagan, professor of pharmacy at the University of Georgia, assistant dean for the MCG program of the UGA College of Pharmacy and study co-investigator.
“That’s an important consideration.”
The drug’s safety and optimal stroke dose are the primary focus of the phase-one clinical trial in stroke patients who arrive at MCG, University of Kentucky or Oregon Health & Science University within six hours of symptom onset and with measurable neurological symptoms.
Newer intravenous antibiotics have replaced minocycline in the United States, but an oral version is used to treat conditions such as acne and rheumatoid arthritis.
One way minocycline fights inflammation is by inhibiting microglial cells, white blood cells activated by a stroke, says Dr. Hess. “When they get activated, they get angry and produce materials that damage the brain.
The inflammatory cascade is bad and good. Early on it’s bad, later on it may actually do some good things,” he says. Typically these microglial cells are sentinel immune cells for the brain, helping eliminate infections and secreting factors that support neurons. However, acutely in a stroke, brain tissue can become their target.
“They are basically cleaning house at first, then later, they are supportive, releasing growth factors and promoting the growth of new blood vessels,” adds Dr. Fagan.
Minocycline also blocks matrix metallo-proteinases, also released during stroke, which destroy the basement membrane of blood vessels. The presence of these enzymes also is a mixed bag.
“If you want angiogenesis – you want to make new blood vessels – you need MMPs around to get rid of the old ones, like tearing down an old building to build a new one,” says Dr. Hess.
However, in patients lucky enough to get the clot buster tPA, the enzyme increases the major risk factor: bleeding.
Dr. Hess notes that while this initial clinical trial is in ischemic strokes, he thinks minocycline also may be useful in hemorrhagic strokes, which account for about 12 percent of strokes, where clearly blocking MMPs would come in handy.
Minocycline also works by blocking apoptosis, or cell suicide, an observation originally made by MCG Cell Biologist Zheng Dong.
The antibiotic’s potential usefulness in protecting brain cells began surfacing in scientific literature within the last few years.
“It was so interesting to us because we knew that a lot of the limitations of other drugs that had been tried in rodents but didn’t work in stroke patients were that they didn’t cross into the brain,” Dr. Fagan says.
“We knew that minocycline did based on previous experiments and the fact that many people who take it for acne or rheumatoid arthritis get dizzy. So we were encouraged by this.
“We wanted something we could give at least three hours after stroke or later. In our studies in animal models, we found at delayed time intervals it was profoundly neuroprotective,” says Dr. Fagan.
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