February 3, 1994
Media Contact:Joann Rodgers
Phone: (410) 955-8659
Johns Hopkins researchers have uncovered the most likely cause of brain cell death in a stroke, according to an article published today in the journal Science.
Using animal nerve cells to reproduce a "stroke in a dish," a research team led by neuroscientist Jie Zhang, Ph.D., found that nerve cells probably die when an overwhelmed repair process uses up too much energy.
When a stroke occurs, blood vessels are damaged and oxygen is shut off, cause a cascade of reactions in brain cells that leads to cell death. "We've long wished for a way to stop the reactions or at least protect brain cells until circulation returns, but that requires an intimate knowledge of what happens in a stroke and when," Zhang says.
The Hopkins research highlights a key part of those reactions and exposes more sophisticated targets for stroke therapy, according to co-researcher Ted Dawson, M.D., Ph.D.
In their experiments, the researchers analyzed extracts of the nuclei of rat brain cells that had been overstimulated by a natural brain chemical. Zhang found high activity of an enzyme, called PARS, that is part of a cell's normal DNA repair system PARS is an unusual enzyme because it takes energy from the cell while preparing DNA for repair.
"We know too much PARS can kill other cell types by depriving them of energy," says Dawson. "But this is the first evidence we've had that it's involved in nerve cells."
'PARS' role in cell death, the study shows, is linked with another stroke-related process - release of the highly reactive molecule, nitric oxide, named "molecule of the year" in 1992 for roles in everything from blood flow to immunity.
"In high concentrations, nitric oxide also causes nerve cell death," Dawson says. Using various combinations of nitric oxide, PARS and DNA in rat-cell nuclei extracts, the researchers found that nitric oxide somehow damages DNA, setting a repair process - and PARS - into action.
The team confirmed this using a "stroke in a dish" - Dawson's phrase for cultures of overstimulated intact nerve cells. By shutting down PARS in the cultured cells with various drugs such as benzamide, the researchers report, they prevented cell damage.
"Other situations, such as Alzheimer's disease, where nerve cells are injured may also involve DNA damage and too much PARS," says Dawson; "this could be the pathway, for example, for amphetamine toxicity."
The scientists are beginning studies to prevent stroke injury in five animals.; by inhibiting PARS,
Valina Dawson, Ph.D., and Solomon Snyder, M.D., are co-researchers in the study funded by NIH grants.