"Because the onset of a stroke can be difficult to detect, many patients do not get treatment for several hours," said James Crapo, M.D., co-author and Chairman of the Department of Medicine at National Jewish. "Our findings suggest that the antioxidant is a promising candidate for stroke therapy because it can prevent damage so many hours after the stroke begins."
Strokes occur when blood supply to the brain is interrupted because blood vessels in the brain either leak or are blocked. Starved of oxygen, the brain cells die. However, cell death continues to occur for many hours, even after blood flow is returned to the brain. Many of the cells that are injured, but not killed by oxygen deprivation, die in the hours following the stroke. Free radicals, highly reactive molecules, kill many of those cells.
The researchers used a synthetic antioxidant, known as AEOL 10150, to neutralize the damaging free radicals and reduce cell death in a mouse model of stroke. AEOL 10150, developed by Dr. Crapo and his colleagues at Duke, mimics the naturally occurring antioxidant superoxide dismutase, but is effective against a wider range of oxygen radicals and lasts longer in the body. Now licensed by Incara Pharmaceuticals Corporation, they have shown promise in preventing damage to cells caused by diabetes and radiation therapy for cancer.
The researchers blocked the middle cerebral artery of rats for 90 minutes. They then injected AEOL 10150 or a placebo into the brains of these mice six hours after the artery had been reopened. The six-hour post-stroke time period has significant clinical relevance. In an unrelated stroke study, 26 percent of patients received treatment within four hours, but 99 percent received treatment within six hours.
When evaluated a week later, animals who received the placebo had an average of 160 cubic millimeters of brain tissue destroyed by the stroke. Animals who received the antioxidant had an average of 92 cubic millimeters of brain tissue destroyed by the stroke, 43 percent less than that the rats who received the placebo.
"There is a significant arc of potentially salvageable tissue surrounding the cells that are killed by the initial stroke," said David S. Warner, M.D., professor of anesthesiology at Duke University Medical Center. "The antioxidant appears to protect this tissue."
The researchers also treated mice with intravenous injections of the antioxidant. Although, this method produced a smaller effect, it reduced both tissue damage and neurological deficit, demonstrating the compound's ability to cross the blood-brain barrier. Mechanistic studies also showed that the antioxidant significantly altered inflammatory gene expression in tissue.