Researchers Discover Molecule that Causes Secondary Stroke

Scientists at the UC College of Medicine have discovered the cause of a deadly type of secondary stroke known as cerebral vasospasm.

A constriction of the blood vessels in the brain, cerebral vasospasm usually occurs three to 10 days following a massive brain bleed known as hemorrhagic stroke. Sixty percent of patients who survive the initial stroke develop vasospasm, and 40 percent of them die from it. 

Vasospasm, says neurology department researcher Joseph Clark, PhD, results from a buildup of toxins caused by bleeding from the initial stroke.

“Normally the cerebral spinal fluid that envelopes the brain carries off wastes and exchanges them for nutrients at what’s called the blood-brain barrier,” Dr. Clark says. “After a hemorrhagic stroke, however, toxins given off by the brain bleed contribute to the development of specific molecules that later causes the constricting vasospasm.”

A research team led by Dr. Clark has now identified the molecules that trigger vasospasm, a breakthrough, he says,  that “raises hopes of developing not only new ways to treat the condition, but also a diagnostic test to determine which hemorrhagic stroke survivors are at greater risk.”

Several spinal fluid components were suspected of causing the vasospasm, Dr. Clark explains. They included hemoglobin, bilirubin and peroxidized lipids, and a group of bilirubin oxidation products that the researchers called BOXes.

Building on Dr. Clark’s earlier studies in rats, the team measured each of the suspect agents in 12 hemorrhagic stroke patients. Within 10 days, four of the group suffered a secondary cerebral vasospasm. The same patients were also found to have elevated levels of bilirubin and significantly higher levels of BOXes.

One of the 12 who had elevated bilirubin, but hardly any BOXes, did not experience a secondary stroke.

When bilirubin is elevated, says team member Gail Pyne-Geithman, PhD, it must be exposed to powerful oxidizers that cause the production of significant amounts of the BOXes. The correlation between elevated BOXes, bilirubin and oxidative stress in this study, she says, was “striking.”

The researchers point out that although their findings are encouraging in terms of developing a diagnostic test and treatment, the number of patients in their study was small and more work is needed to confirm that vasospasm is more likely to occur in bleeding-stroke patients who have elevated levels of BOXes.

The study is reported in the March 23, 2005, online edition of the Journal of Cerebral Blood Flow and Metabolism.

Co-authors also include Chad Morgan, MD, Kenneth Wagner, PhD, Elizabeth Dulaney, Janice Carrozzella, RN, Daniel Kanter, MD, and Mario Zuccarello, MD.

This research was funded by The National Institutes of Health and the Neuroscience Institute in Cincinnati.

The university, in partnership with the Health Alliance of Greater Cincinnati, established The Neuroscience Institute in 1998 as part of an effort to build upon its national reputation for excellence in neuroscience. The institute includes or is developing research centers that focus on the main diseases of the brain and nerves such as stroke, brain tumors, brain trauma, Parkinson's, Alzheimer's, epilepsy, ALS and multiple sclerosis.