Instead of killing damaged cells directly as once believed, an immune molecule works behind the scenes, shutting down receptors within neurons that normally welcome a separate life-saving protein with open arms, a team of scientists says.
The discovery, reported in the Aug. 17 issue of the Proceedings of the National Academy of Sciences, sheds new insight on the cross-talk of two proteins-- insulin-like growth factor, a life-promoting molecule, and an inflammatory cytokine known as tumor necrosis factor alpha (TNF)-- within damaged cells. The findings could become important in the treatment of brain injuries and of Alzheimer's, stroke, multiple sclerosis and AIDS dementia, all of which involve neurodegeneration.
The brains of animals with these injuries and diseases have been injected with large amounts of IGF-I, a pharmaceutical replica of natural growth hormone produced by the liver, to encourage the healing of damaged cells. But, for unexplained reasons, results have not been 100 percent positive.
"Our findings are about life and death and survival of damaged neurons," said Keith W. Kelley, an animal scientist at the University of Illinois and president of the PsychoNeuroImmunology Research Society ( http://www.pnirs.org ).
"Previously, it was believed that IGF and TNF acted completely separately, with IGF inducing life and survival, and TNF simply killing cells directly. Instead TNF is more effective by killing neurons indirectly by scrambling the signal so IGF cannot bind to target cells and produce a survival enzyme", said Homer D. Venters, a student in the M.D.-Ph.D. medical scholars program in the U. of I. College of Medicine at Urbana-Champaign.
The team's findings are based on in vitro experiments with neurons cultured from normal mice. In mammals, IGF induces muscle protein synthesis, enhancing growth and weight gain, except in the presence of TNF, which is produced by immune cells in both the immune system and the brain. In neurons, the activity is similar; IGF works to save damaged cells, but its ability quickly diminishes when TNF is added into the mix.
"When there is an insult to the brain, there are bad guys like this molecule TNF that has been thought to directly kill neurons," said Robert Dantzer of France's Institute Francois Magendie. "This paper shows that this is not the way the bad guys work. What the bad guys are doing is preventing the effects of the good guy-- the growth hormone that normally sits there and helps the cell to survive."
Putting the knowledge into clinical use, however, will take time. "Drug delivery is the key," Kelley said. "Targeting more IGF specifically to the brain may not be the answer. It may be that we should target the TNF with an inhibitor so the naturally occurring IGF can work better."
The project is part of a research program that began in 1997 and links the U. of I. and the National Center for Scientific Research in France. Funding came from the National Institutes of Health and the Japanese Ministry of Agriculture, Forestry, and Fisheries.
(Editor's Note: Copies of the paper are available to reporters from the PNAS news office, which may be reached by phone, (202) 334-2138, or through e-mail at [email protected].)
The above story is based on materials provided by University Of Illinois At Urbana-Champaign. Note: Materials may be edited for content and length.
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