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Research Newsletter-Spring/Summer 2007

LPI 10th ANNIVERSARY COLLOQUIUM

Free radicals, antioxidants, and Lou Gehrig: The brain is a terrible thing to waste

Joseph Beckman, Ph.D.
Ava Helen Pauling Chair and Principal Investigator, Linus Pauling Institute;
Professor of Biochemistry and
Biophysics, Oregon State University

Despite a remarkable recent increase in research spending by the National Institutes of Health (NIH) to investigate human health and disease, health care costs in the U.S. continue to rise by 15% per year and will rise from 15% to 23% of the GNP in the next ten years with the aging of the population. Primary prevention is by far the most cost-effective means to control health care costs and to improve public health. The goal of primary prevention is to improve human health and reduce susceptibility to disease before patients end up in the hospital needing expensive medical treatments.

According to the National Institute of Environmental Health Sciences (NIEHS), environmental stresses, age, and individual susceptibility are major factors influencing human health and disease mechanisms. Our health status is a delicate balance between damage and repair mechanisms. When we are young, our bodies are better able to handle damage from carcinogens (cancer-causing agents), infection, UV radiation, oxidative stress, and other endogenous and environmental insults. However, as we age, our repair systems become less able to manage these stresses. Aging, in simple terms, is the body's decreasing ability to deal with stress. We do not have control over some individual susceptibility factors, such as age, gender, and genetics. Others, such as diet and lifestyle, can be modified. At the Linus Pauling Institute, we are examining the roles of micronutrients and their abilities to improve our individual resistance to disease.

Antioxidants have been linked to protective health benefits in several population-based research studies in the development of neurological and neurodegenerative diseases. A long-term study tracked almost one million American adults for over 15 years. One of the factors studied was regular vitamin E intake. Compared to people who never took vitamin E supplements, individuals taking vitamin E for two to ten years had a 41% decreased risk of developing amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease). For individuals regularly taking vitamin E for over ten years, the risk of developing ALS was reduced by 62%. This suggests that regular, long-term intake of vitamin E significantly reduces the risk of developing ALS. Another study of elderly residents of Cache County, Utah, showed a decreased incidence of Alzheimer's disease associated with regular intake of vitamins E and C taken simultaneously. Delaying the onset of Alzheimer's by just five years is estimated to save the equivalent of the entire NIH budget in health care costs.

Neurological diseases, such as ALS, Alzheimer's, Parkinson's, and mad-cow disease, share many common features. All involve the improper configuration of proteins and perhaps the binding of copper and zinc in inappropriate locations.

An important antioxidant protective enzyme related to ALS is superoxide dismutase or SOD. SOD works to remove superoxide, a free radical compound. While superoxide is not the most dangerous compound itself, it can combine with nitric oxide (a compound important for the relaxation of blood vessels) to form peroxynitrite, a very destructive oxidative compound. We and others have found that a certain number of ALS cases are related to mutations of the SOD gene. These mutations slightly weaken the ability of SOD to hold on to its zinc atom in the enzyme's active site, leading to conditions that foster the formation of superoxide and peroxynitrite.

Our research shows that peroxynitrite affects astrocytes, cells in the brain that support motor neurons (nerves responsible for muscular movement). This leads to the degeneration of motor neurons as observed in patients with ALS. Our research suggests that peroxynitrite does not simply damage astrocytes. The destructive cycle propagates itself by activating the astrocytes, causing these formerly supporting cells to become destructive to even more motor neurons.

Our collaborators in the Luis Barbeito lab in Uruguay have shown that a protein called Nuclear factor-erythroid 2-related factor 2 (Nrf2) and increased glutathione (an antioxidant produced in the body) can reduce the effects of damaging astrocytes on motor neurons. This mechanism also has implications on Parkinson's and Alzheimer's, since those diseases have similar pathologies.

Last updated May 2007