The clinical problem with nerve growth factors, or neurotrophins, is that they are somewhat misnamed. They do indeed promote the growth of some brain cell types - but the death of others.

That has been one barrier to using them therapeutically, since saving neurons while killing off their myelin sheath is not what one might term a promising strategy overall.

But in the May 17, 2006, issue of the Journal of Neuroscience, researchers reported on using a virtual screening method to identify compounds that activate the p75 neurotrophin receptor. The compounds promoted cell survival in several different brain cell types, including oligodendrocytes, which usually are nudged toward apoptosis by neurotrophins themselves.

The scientists, from the Veteran's Affairs Medical Center, the University of California at San Francisco, the University of North Carolina at Chapel Hill, Ohio State University and Cornell University, used a combination of in silico and in vitro screening, as well as old-fashioned chemical expertise, to get their leads. They first created a model of part of a neurotrophin known to interact with the p75 neurotrophin receptor, and then tested more than 1 million virtual molecules for potential binding action. A group of 800 candidates was reduced to about 60 by visual inspection, and eventually, based on both in vitro screening and theoretical considerations, two compounds were chosen that had the greatest potential to be turned into drugs.

Inhibitors usually are easier to find than activators, since it is a less precise endeavor to gum up an interaction than to mimic it. Lead author Stephen Massa, neurologist at the Veteran's Affairs Medical Center, did have some ideas about why his team was able to generate activators.

"A lot of it had to do with post-processing," he told BioWorld Today, adding that what allowed the scientists to pick activators was "almost chemical intuition, but informed massively by data." Nevertheless, he said his team had been "surprisingly successful" in generating the activators. His team is working on quantitating that chemical intuition to make the process reproducible.

The scientists found that their compounds increased neuronal survival in cell cultures, and that it did so by interacting with the p75 neurotrophin receptor. In the hippocampus, their effects were similar to those of nerve growth factors. But the compounds also increased survival of oligodendrocytes, which form the myelin sheath that lets neurons pass on electrical signals. The myelin sheath is damaged in multiple sclerosis and can contribute to paralysis after spinal cord injuries.

Massa said that it is unclear at this point why the activators his team described in the paper don't kill oligodendrocytes, but there are several possibilities, though he stressed that all are speculative: The compounds might not bind to sortilin, a pro-apoptotic coreceptor, or they could prevent the binding of proneurotrophin, the precursor form of neurotrophin that does the actual damage.

Massa and his colleagues plan on having a hand in commercializing their discoveries themselves; he said the plan is to start a company and license back the technology from UNC, which holds the rights to the discoveries. The scientists hope that the compound might prove useful in Alzheimer's disease, since hippocampal neurons, which are important for memory and damaged in Alzheimer's, have p75 neurotrophin receptors. In Alzheimer's disease, proneurotrophins appear to bind to hippocampal neurons and induce cell death. But the compounds also could prove useful in other chronic diseases such as multiple sclerosis and ALS, and in acute conditions like head or spinal cord injury, or stroke.

"All of these are on the table" as possible indications, Massa said.