Oct. 1, 1997 By further tracking nitric oxide's actions in the brain, Johns Hopkins scientists report they have figured out what may be a universal sequence of biochemical events from stroke to brain cell death.
Cell death appears to result from the overactivation of an enzyme called poly (ADP-ribose) polymerase, or PARP, which lethally depletes energy sources from the cells, according to Valina Dawson, Ph.D., associate professor of neurology. When she and her colleagues induced strokes in mice genetically engineered without a PARP gene, brain damage was dramatically reduced in comparison to a group of unaltered mice.
"Nitric oxide has long been known to play a role in neuronal damage after stroke, and now it seems that a candidate pathway for that injury is DNA damage leading to unusual PARP activation," Dawson reports in the October issue of Nature Medicine. Nitric oxide does its damage by sabotaging the DNA of nerve cells. The DNA nicks and breaks activate PARP, which is normally, for the most part, dormant, she says.
"Clinically, our work suggests that inhibiting PARP may spare nerve cells from energy loss, thus preventing irreversible damage and providing protection," says Solomon Snyder, M.D., distinguished service professor and director of the Department of Neuroscience and an author of the paper. "The reduction in brain damage from stroke we observed among the mice without PARP exceeds the protection reported with any known stroke treatment."
Paradoxically, in cases of minor damage, PARP acts as a relief squad, activated to make repairs. But with more substantial damage, such as severe loss of blood during stroke, PARP can be overactivated. When this happens, it uses up NAD, the substance PARP acts on, and ATP, the major energy source of all cells, causing the cell to die of energy depletion.
In the study, researchers first compared brain tissue from the so-called "knockout" mice, bred in Austria without a PARP gene, to unaltered mice to measure toxicity caused by interaction with other brain chemicals released in cases of neurological damage. The tissue from the knockouts were completely resistant to neurotoxicity. In tissues from the unaltered mice, however, approximately 65 percent of the cells were destroyed.
They then induced experimental strokes in the mice to evaluate the extent of resulting brain injury. Tissue damage in the genetically altered mice was 80 percent less than in the unaltered mice.
"The reduction in stroke damage in PARP knockout animals suggests that PARP inhibitor medications will be useful for treating strokes," Snyder says.
Stroke is the third leading cause of death and disability, affecting 3 million people each year. It occurs when a blood vessel bringing oxygen and nutrients to the brain bursts or is clogged by a blood clot or some other particle. Because of this rupture or blockage, part of the brain doesn't get the flow of blood it needs, and the nerve cells in that section start to die within minutes. Brain damage from a stroke can diminish the senses, speech and the ability to understand speech, behavioral patterns, thought patterns, and memory. Paralysis on one side of the body is common.
Michael Muskowitz and colleagues at the Massachusetts General Hospital have independently replicated these findings, Snyder says, and will be publishing their results in the near future.
The study's other authors were Mikael J.L. Eliasson; Kenji Sampei, M.D.; Allen S. Mandir, M.D.; Patricia D. Hurn, Ph.D.; Richard J. Traystman, Ph.D.; Jun Bao, Ph.D.; Andrew Pieper; Zhao-Qi Wang, Ph.D.; and Ted M. Dawson, M.D., Ph.D..
Johns Hopkins has previously licensed the rights for PARP inhibitors to Guilford Pharmaceuticals in Baltimore. Under the terms of the previous license agreement between the Johns Hopkins University and Guilford, Snyder, Valina Dawson and Ted Dawson are entitled to a share of sales royalties received by the University from Guilford.
The University owns stock in Guilford, with Snyder and Ted Dawson having an interest in the University share under University policy. The University's stock is subject to certain restrictions under University policy. Snyder also serves on the Board of Directors and the Scientific Advisory Board of Guilford, he is a consultant to the company, and he owns additional equity in Guilford. This arrangement is being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.
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