In culture, the compounds bind with a receptor found in the brain and spinal cord called p75NTR. In the body, p75NTR is a binding site for molecules known as neurotrophins, which normally promote the growth and development of neurons and other brain cells but, according to other studies, can also kill them, depending on how and where they bind to a cell.
Evidence suggests neurotrophins may play a role in Alzheimer's disease and other brain diseases and conditions, says lead and co-corresponding author Stephen M. Massa, MD, PhD, a neurologist at SFVAMC. In Alzheimer's disease, some of the brain cells that die - including neurons in the hippocampus, which plays an essential role in memory - express the p75NTR binding site, indicating they may be dying because neurotrophins are binding to them, says Massa.
Because the new compounds bind with p75NTR in place of neurotrophins, they may provide a means of preventing damage that neurotrophins would otherwise be causing in Alzheimer's disease and other neurodegenerative diseases and conditions, he says.
"In binding to p75 in place of neurotrophins, these compounds promote the survival of neurons, including hippocampal neurons, in culture," noted Massa, who is also a clinical assistant professor of neurology at the University of California, San Francisco.
The study appears in the May 17, 2006 issue of the Journal of Neuroscience.
Massa noted that the protective quality of neurotrophins has led other researchers to explore their potential therapeutic value; however, their destructive attributes have so far prevented their development as medicines.
"When Dr. Rita Levi-Montalcini won the Nobel Prize for Medicine in 1986 for her discovery of neurotrophins, she remarked that the next critical milestone would be to develop pharmacological approaches that could achieve the actions of these potent proteins and make possible their potential application in the clinic," said co-corresponding author Frank Longo, MD, PhD, of the University of North Carolina, Chapel Hill at the time of the study and currently of Stanford University. "Our team is thrilled to have been able attain this decades-long goal."
In further tests, the research team discovered that the compounds can also inhibit the death of oligodendrocytes, the cells in the central nervous system that form myelin, the insulating sheath surrounding nerve cells.
Normally, oligodendrocytes die when exposed to proneurotrophins - precursor forms of neurotrophins that have been implicated as agents of tissue damage in multiple sclerosis, spinal cord injury and Alzheimer's disease. "The compounds were able to inhibit the processes induced by proneurotrophins that lead to oligodendrocyte death," recounted Massa. To identify the compounds, the researchers developed an innovative computer-based method.
They created a virtual three-dimensional model of a section of a neurotrophin known to interact with p75NTR, and then tested virtual representations from a library of over one million known molecules for potential binding action. A group of 800 candidate molecules was eventually reduced to four, of which two were chosen for extensive study because they showed the greatest potential to be turned into drugs.
Currently, the research team is investigating a number of other promising compounds that they identified using the same method. "The range of diseases to which this group of compounds might have applicability is enormous," said Massa.
"We have already started to test them in preclinical studies of neurological disorders," added Longo.
Co-authors of the study were Youmei Xie, MD, PhD, Tao Yang, PhD, and Laura A. Moore, BA, of the University of North Carolina-Chapel Hill; Anthony W. Harrington, PhD, Mi Lyang Kim, BA, and Sung Ok Yoon, PhD, of Ohio State University; and Rosemary Kraemer, PhD and Barbara Hempstead, MD, PhD, of Cornell University.
The study was funded by grants from the Institute for the Study on Aging, the Alzheimer's Association, the French Foundation, the National Institutes of Health, and the Department of Veterans Affairs.
SFVAMC has the largest medical research program in the national VA system, with more than 200 research scientists. All SFVAMC principal investigators have dual appointments as faculty members of UCSF.
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