Cell death following blood 'reflow' injury tracked to natural toxin

November 29, 2006

Researchers at Johns Hopkins have discovered what they believe is the "smoking gun" responsible for most tissue and organ damage after a period of blood oxygen loss followed by a sudden restoration of blood oxygen flow.

Working with mice, the Hopkins team found that the sudden oxygen bath triggered by restored blood flow causes cells to make a chemical so toxic it kills the cells. The work was published in two papers in the Proceedings of the National Academy of Sciences last week.

Although not sure why it happens, the Hopkins scientists believe the toxic chemical, PAR-polymer, acts like a molecular sledgehammer, or a death switch. "We've found evidence of it in cells following all types of injury," says Ted Dawson, M.D., Ph.D., the Leonard and Madlyn Abramson Professor of Neurodegenerative Diseases, professor of neurology and co-director of Hopkins' Neuroregeneration and Repair Program in the Institute of Cell Engineering (ICE).

The research team has named the cell death process caused by PAR-polymer "parthanatos," after Thanatos, the personification of death from Greek mythology.

To establish that PAR-polymer is indeed the culprit in the kind of reperfusion injuries long linked to heart attacks, strokes and a variety of blood vessel injuries, the researchers pumped mouse nerve cells full of PAR-polymer. The cells died, but to be sure PAR-polymer (and not something else) killed them, they examined the brains of mice engineered to lack an enzyme that chews up and gets rid of PAR. These mouse brains contained twice as much PAR-polymer as those of normal mice.

After the researchers induced a blood clot injury like a stroke, the same mice showed a 62 percent increase in the area of brain damage compared to normal littermates. Mice that contain more of the PAR-chewing enzyme suffered less brain damage than their normal littermates.

To figure out what triggers the death switch, the researchers tracked PAR-polymer's journey after cells made it. After 15 minutes, PAR-polymer hadn't gone anywhere. But after 30 to 60 minutes, the researchers discovered that much of it traveled right to areas where the switch normally resides.

The fate of the cell is irreversible once PAR-polymer sets off the trigger, says Valina Dawson, Ph.D., professor of neurology, co-director of the Neuroregeneration and Repair Program and author of the papers. "If we could figure out how to block PAR-polymer, we could design drugs that protect the switch and prevent cells from dying after heart attacks, stroke or other injuries," she says.
-end-
Researchers were supported by grants from the National Institutes of Health and the American Heart Association.

Authors of the two papers are Shaida Andrabi, No Soo Kim, Seong Woon Yu, Hongmin Wang, David Koh, Masayuki Sasaki, Judith Klaus, Takatshi Otsuka, Zhizheng Zhang, Raymond Koehler, Patricia Hurn, Valina Dawson and Ted Dawson, all of Hopkins, and Guy Poirier of Laval University Medical Research Center at Centre Hospitalier Universitaire de Quebec in Canada.

On the Web: http://www.neuroice.org/

Johns Hopkins Medicine

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