Researchers have taken a first snapshot of how a class of highly reactive molecules inflicts cellular damage as part of aging, heart disease, stroke, cancer, diabetes, kidney disease and Alzheimer’s disease to name a few. According to a study published in the journal Cell, researchers have discovered a tool that can monitor related damage and determine the degree to which antioxidant drugs effectively combat disease.

Reactive oxygen species (ROS), which include free radicals, are highly reactive molecules that force change upon many molecules they encounter. The body uses ROS to signal for wound healing and to destroy invaders. Excess amounts, however, damage sensitive cell components, including proteins and DNA, in a process called oxidative stress. ROS are kept in check by the body’s natural antioxidants, but when uncontrolled can lead to disease.

“Our study provides a better glimpse of why a cell under assault by disease makes 10 times as many reactive oxygen species as the same cell when healthy,” said Shey-Shing Sheu, Ph.D., professor of Pharmacology and Physiology at the University of Rochester Medical Center, and a study author. “We have discovered a chemical tool for investigating how diseases cause damage, mitochondrion by mitochondrion, which should represent a tremendous advance as both a disease biomarker and for drug discovery.”

The research team looked at one kind of oxidative stress in particular: that caused when the oxygen supply to the heart is initially cut off (e.g. during a heart attack or stroke) and then re-established. When heart muscle cells were exposed to a non-oxygen solution for six hours, superoxide flash frequency decreased four-fold, to one event per 100 seconds. Upon re-introduction of oxygen, superoxide production increased eight-fold, confirming past work that re-oxygenation after a heart attack comes with a burst of destructive and uncontrolled superoxide production and oxidative stress.

Efforts to develop antioxidant drugs (e.g. vitamin E) to treat diseases of increased oxidative stress have met with limited success to date because they tried to eliminate ROS, rather than maintain the right amount, Sheu said. He established the Mitochondrial Research & Innovation Group (MRIG) at the Medical Center in 2002 with the goal of designing therapies to deliver precise amounts of antioxidants to the mitochondria of diseased cells only. MRIG teams are, for example, screening through compounds to confirm that oxidative stress can be reversed by mitochondria-specific drugs. The new superoxide flash probe will provide a powerful tool for determining the effectiveness of new classes of antioxidant drugs in reducing superoxide production at the right place and time.

The “birthday” for superoxide flashes came in June of 2003 in the lab of Robert Dirksen, Ph.D., associate professor of Pharmacology and Physiology at the Medical Center, when Linda Groom observed spontaneous bursts of fluorescent light using the newly developed protein-based superoxide indicator. The current paper’s lead author was Wang Wang, Ph.D. formerly a postdoctoral fellow at the National Institute on Aging at the National Institutes of Health. Aiwu Cheng, Jinhu Yin, Weidong Wang, Edward Lakatta and Mark Mattson also contributed from the NIH, as did Joseph Kao from the University of Maryland. Also contributing from Peking University in Beijing were Huaqiang Fang, Wanrui Zhang, Jie Liu, Xianhua Wang, Kaitao Li, Peidong Han, Ming Zheng, and Heping Cheng, the corresponding author.

“One co-author on the current paper, Dr. Cheng of Peking University, 15 years ago published a seminal study regarding local calcium release events, or calcium sparks,” Dirksen said. “This study has been cited more than 900 times and has provided a major contribution to our understanding how the heart beats and why it fails. We believe that our serendipitous discovery of local mitochondrial superoxide flash events could be even more important because superoxide flash frequency may provide an accurate, real-time picture of how uncontrolled oxidative stress contributes to the progression of several, debilitating cardiovascular and neurological diseases.”

Posted: 07|28|08 at 10:19 am. Filed under: News.