In stroke and various neurodegenerative disorders, such as Alzheimer's disease and Lou Gehrig's disease, glutamate, an amino acid found in high quantities in the brain, is thought to accumulate. At normal concentrations, glutamate acts as a neurotransmitter that nerves use to communicate. However, at excessive levels glutamate is toxic, resulting in over stimulation of nerve cells, known as excitotoxicity, and causing excessive stress on the nerve cells eventually ending in cell death. Studies described in this report suggest that NEPPs (short for NEurite outgrowth-Promoting Prostaglandins), compounds that accumulate in nerve cells, prevent nerve damage by activating the Keap1/Nrf2 pathway that regulates the production of antioxidants which relieve cells of damaging free radicals that result from excitotoxicity.
"This is the first reported evidence that this protective response can be activated directly in nerve cells to release antioxidants and counter oxidative stress," said Stuart Lipton, M.D., Ph.D., Director of the Del E. Webb Center for Neurosciences and Aging at the Burnham Institute and senior author of the study. "These findings provide support for further investigation of NEPP drugs to potentially treat ischemic stroke, multiple sclerosis, Alzheimer's disease, Lou Gehrig's disease and other neurodegenerative disorders."
Researchers found that NEPPs were able to activate a pathway in nerve cells that is designed to protect against oxidative and nitrosative stress (which produces free radicals) and excitotoxicity. This pathway, known as Keap1/NrF2, regulates the production of natural antioxidants, such as bilirubin, that can protect against oxidative stress resulting from ischemic stroke and degenerative disorders.
A paper detailing the findings of this study, entitled "Activation of the Keap1/Nrf2 Pathway for Neuroprotection by Electrophilic Phase II Inducers" (Satoh, et al.), will be published in the January 17th issue of the Proceeding of the National Academy of Sciences. In addition, the findings will be made available by expedited publication at the journal’s website on January 10th.This research was supported with grants from the National Institutes of Health.
About the Burnham Institute for Medical Research
The Burnham Institute for Medical Research, founded in 1976, is an independent not-for-profit biomedical research institution dedicated to advancing the frontiers of scientific knowledge and providing the foundation for tomorrow's medical therapies. The Institute is home to three major centers: the Cancer Center, the Del E. Webb Neuroscience and Aging Center, and the Infectious and Inflammatory Disease Center. Since 1981, the Institute's Cancer Center has been a member of the National Cancer Institute's prestigious Cancer Centers program. Discoveries by Burnham scientists have contributed to the development of new drugs for Alzheimer's disease, heart disease and several forms of cancer. Today the Institute employs over 725, including more than 550 scientists. The majority of the Institute's funding derives from federal sources, but private philanthropic support is essential to continuing bold and innovative research. For additional information about the Institute and ways to support the research efforts of the Institute, visit www.burnham.org.
Journal
Proceedings of the National Academy of Sciences