Oct. 23, 2002 Researchers at the National Institutes of Health have developed several drug candidates that show promise in animal studies in protecting the brain against sudden damage from stroke, with the potential for fighting chronic neurodegenerative conditions like Parkinson's and Alzheimer's disease. The drugs, called p53 inhibitors, attack a key protein involved in nerve cell death and represent a new strategy for preserving brain function following sudden injury or chronic disease, according to the researchers.
Their findings will appear in the Nov. 7 print issue of the Journal of Medicinal Chemistry, a peer-reviewed publication of the American Chemical Society, the world's largest scientific society.
"This is a completely new therapeutic strategy for Alzheimer's and other neurodegenerative diseases, which warrants further assessment to allow it to move to clinical trials," says Nigel H. Greig, Ph.D., a researcher with the National Institute on Aging's Intramural Research Program in Baltimore, Md., and chief investigator for the study. "If it works, it could provide a new treatment approach for a wide range of neurological diseases."
The research is limited to cell and animal studies for now, but if all goes well, human clinical trials could begin in two to three years, Greig says. The new drugs could provide relief for millions of Americans who suffer from mental and physical decline due to neurological damage and offer hope to those who are at increased risk due to advancing age.
Drugs currently used to treat neurological disease and injuries provide temporary relief of symptoms but do not stop or slow the underlying neurodegenerative process. The new experimental drugs, by contrast, target the common, underlying cause of this destructive process: the death of brain cells.
"By turning off cell death, you rescue brain cells from lethal insult," Greig says. He compares other drugs to "bandages" that help alleviate brain damage after it occurs, whereas p53 inhibitors act as "seat belts" that help prevent damage from occurring in the first place.
The main target of these drugs, p53, is a common protein found in cells that triggers the biochemical cascade of events leading to cell death. As cells die, new, healthy ones normally replace them. But in the diseased or injured brain, cell death can cause devastating damage, as brain cells cannot regenerate. The researchers theorized that by inactivating the protein temporarily, further brain damage might be prevented.
The researchers identified one compound, called pifithrin-alpha (PFT), which was shown in previous studies to inhibit p53. They then designed, synthesized and tested analogues of this compound to see whether they would work against cultured brain cells and animal models of neurodegenerative disease.
In laboratory tests, brain cells exposed to a series of toxic chemicals survived longer when given the inhibitor compound. In subsequent tests using a rodent model of stroke, the severity of stroke damage was significantly decreased in animals that received the inhibitor compounds compared to those that did not receive it, the researchers found.
Evidence for the drugs' potential effectiveness against chronic neurodegenerative diseases is growing. In a related study, the researchers found that the drugs appear to prevent nerve damage in a mouse model of Parkinson's disease.
In another study, the researchers showed that the compounds protect brain cells against beta amyloid, a toxic protein associated with Alzheimer's disease. They are now planning to test the experimental drugs in animal models of the disease.
The new drugs will probably first be used to treat stroke, brain injury (from sports and motor vehicle accidents) or other conditions characterized by sudden brain trauma, the researchers say. If the compounds prove safe, they could later be extended to long-term diseases like Alzheimer's, Parkinson's, and Lou Gehrig's (amyotrophic lateral sclerosis, or ALS).
The researchers caution that they need to first make sure that the inhibitors don't cause side effects in other cells of the body. Other studies show that mice that have no p53 have an increased incidence of cancer, while those that have high levels of p53 experience premature aging.
"You have to have just the right balance," Greig says. Ideally, the compounds will work only temporarily and will then be broken down by the body.
Greig and his associates are currently testing various drug analogues to see which ones work the best. Once developed, the drugs can either be used as an oral pill or intravenously, depending on how quickly they need to be administered.
The National Institute on Aging provided funding for this study.
Dr. Greig's associates in this study were Xiaoxiang Zhu, Ph.D., Qian-sheng Yu, Ph.D., Roy G. Cutler, M.S., Carsten W. Culmsee, Ph.D., Harold W. Holloway, B.S., Mark P. Mattson, Ph.D., all of the NIA's Intramural Research Program; and Debomoy K. Lahiri, Ph.D., of Indiana University School of Medicine in Indianapolis, Ind.
Nigel H. Greig, Ph.D., is chief of the Drug Design & Development Section in the Laboratory of Neurosciences at the National Institute on Aging's Intramural Research Program in Baltimore, Md.
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