Paves the Way for Novel Neuroprotective Treatments
By Aman Shah, MD
WebMD Medical News
Reviewed by Michael W. Smith, MD
Aug. 13, 2001 -- According to animal research described in the Aug. 9 issue of Nature, patients with Alzheimer's and other brain diseases might benefit from erythropoietin (EPO). The study shows that the hormone, which normally regulates red blood cell production, is released by the brain in response to oxygen deprivation or similar stress and may have important neuroprotective effects.
"EPO increases the oxygen-carrying capacity of the blood and may also protect against stroke and other forms of brain injury," senior author Stuart A. Lipton, MD, PhD, director of the Center for Neuroscience and Aging of the Burnham Institute in La Jolla, Calif., tells WebMD. "Developing drugs to treat brain disease takes 10-15 years, because 99% turn out to be unsafe. We're testing drugs that we know are safe, so we're that much more ahead of the game."
"The model we used was to insult nerve cells [in rats] with glutamate, a free radical that is the final common pathway in many brain diseases including Alzheimer's and other dementias, stroke, and head trauma. Glutamate is the major excitatory chemical in the brain, causing a lot of secondary damage in nerve cells," says Lipton.
"This is the first paper showing a specific receptor for EPO in the brain, found only in nerve cells and not in glia. The signaling pathway triggered by EPO allows cross-talk between two different known signaling pathways involving two neuroprotective genes. EPO is involved in preconditioning the kidney and brain to protect them against free radicals generated by hypoxia," says Lipton, who is also an adjunct professor at the Salk Institute, Scripps Research Institute, and the University of California, San Diego.
Previous studies have shown that short periods of hypoxia and ischemia can be neuroprotective against apoptosis due to nitric oxide or glutamate and that such ischemia results in the induction of EPO. Preconditioning with EPO is, hence, likely to be clinically feasible, particularly since EPO passes the blood-brain barrier.
"Difficulty clearing glutamate is the culprit in brain damage from most causes, so we've been looking for ways to protect against it," says Lipton. "If EPO looks promising in animal models for stroke, Alzheimer's, Huntington's, Lou Gehrig's disease, and MS, we can start human testing."
"This work is an interesting and important extension of our previous work that showed that gene and protein expression changes are essential to the triggering of hypoxic-ischemic preconditioning," Patric K. Stanton, PhD, associate professor of neuroscience and neurology at Albert Einstein College of Medicine in the Bronx, N.Y., tells WebMD. "This study is an important advance in beginning to understand the cellular chemistry by which hypoxia-ischemia makes neurons resistant to future insults, a phenomenon called 'hypoxic-ischemic preconditioning.'
"If we can understand and develop treatments that [work the same way], we could make our brains more resistant to stroke-induced damage, perhaps even after strokes have occurred," says Stanton, who was not involved in the study.
"This research paves the way for clinical trials of EPO in stroke patients, and for the development of novel drugs that stimulate [similar pathways] in the brain," says Mark P. Mattson, PhD, who reviewed the study for WebMD. He is chief of neurosciences at the National Institute on Aging in Bethesda, Md.
"There will be several hurdles to cross, because EPO [has] diverse effects on various types of cells in the brain including blood vessel cells and immune system cells," says Mattson. "The ideal drug for stroke would therefore activate EPO ... only in nerve cells so as to avoid possible adverse side effects."