The central nervous system - made up of brain and spinal cord - never forgets an insult. Human nerve cells do forget how to regenerate, as witness Christopher Reeve's paralysis, after his horse threw him at a jump. Neurologists know that neurons lose their ability to regenerate because of some signal during embryonic development.

"Neurobiologists have been trying to understand for a long time why the brain doesn't repair itself after injury," observed research neurobiologist Ben Barres, a professor at Stanford University Medical School. "A lot of research over the last 20 years," he said, "has shown that a big part of the problem is the glial cells - nursemaids in the CNS - which are inhibitory to regenerating an axon.

"And it's known," Barres continued, "that the peripheral nervous system outside the CNS does have the capacity to regenerate. There the glia are actually supportive. The thought has been that one way to enhance regeneration would be to go to drugs, for instance, that would overcome this inhibition."

Barres is senior author of a paper in today's issue of Science, dated June 7, 2002. Its title: "Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells."

"The first finding of the paper," he told BioWorld Today, "is our discovery that the older neurons are losing their ability to regrow their axons. This comes about as a result of retinal maturation - in particular, because of another retinal neuron called an amacrine cell. They are telling the retinal ganglion cells to go into a dendritic growth mode. That is, inducing a shift in the growth ability of the neuron from its axon to its dendrites. After the axons get to their target in the rest of the brain, they then need to make dendrites for the other retinal neurons' synapses.

"What we set out to address in particular," Barres went on, "is the obvious possibility that maybe the neurons themselves in the adult nervous system have a limited ability to repair or replace lost or damaged neurons. It's been known for a long time that the developing central nervous system does have a pretty good capacity to generate. But as the CNS system gets older, the neuronal synapse loses this ability to regenerate. One explanation for that is, as the nervous system gets older, the neurons themselves change - get less able to self-repair."

Retinal Neurons: Window To The Brain

"We developed methods to separate the neurons from the glias," Barres recounted. "We could purify retinal neurons because they're a classical system for studying this regeneration problem. The retina is part of the brain, and retinal ganglion cells appear to have the same lack of regenerative ability. There's just one neuronal projection from the retina to the optic nerve. And we found a way to keep rat retinas alive in the culture dish, at different ages. Besides that, we transplanted the old and young neurons directly into a developing brain, to ask whether we would still see a difference, and we did. The old ones grew slowly, even with the developing brain, which would be a strong supporting environment for growth.

"That way we could directly ask: What is the ability of ganglion retinal cells at different ages to regrow their axons? And we found to our amazement an enormous difference in the capacity of young and old neurons to grow. The young neurons - 20 days into gestation - are able to regenerate axons at an incredibly rapid rate: 10 times quicker than the older eight-day postnatal neurons in the adult rats. That was the main finding of our Science paper.

"Its most important implication," Barres pointed out, "is that the failure of the brain to repair itself after injury has at least two explanations: one, that glial cells are inhibitory, but two, as our results indicate, that there's a second problem, which is that the older neurons of the CNS have lost the intrinsic ability to rapidly regenerate their axons. So even if we could develop drugs that overcame all this glial inhibition, we'd still have the problem that the neurons are going to grow slowly.

"In fact," Barres went on, "my grad student, Jeffrey Goldberg, calculated that if a drug is found that will now allow Christopher Reeves' axons to start growing back down his spinal cord, if those neurons grow at the same slow rate as our retinal neurons do, it would take 10 years for the axons to grow from the top of Christopher Reeves' spinal cord back down to the other end.

"Neurons intercommunicate via axons and dendrites. Amacrine cells drive dendrites into growth mode. It also appears from our work that after the cells decide to shift from an axonal to a dendritic growth mode, that's a permanent change. It's apparently irreversible by any maneuver that we tried, to make the cell revert to its rapid growth mode. So we assume - if that's possible - it's going to involve some sort of molecular manipulation or drug."

If Molecules Can't Hack It, Try Drugs

"We're working very much in that direction," Barres said, "doing genomic experiments in which we are purifying large numbers of the old and new neurons, and extracting their RNA. Now, using microarray profiling, we're comparing genes expressed in the old, adult neurons, with the new prenatal ones. And whether any of the regions change as a result of aging, or of this axon-to-dendrite switch. We have identified at least 20 genes that turn on and off as a result of this shift. These are genes, as yet unpublished, expressed throughout the brain. Presumably, since this change appears to be a permanent one, we're going to have to find gene changes that account for this loss of ability. So we hope to zoom in fairly quickly on this molecular mechanism that turns off the regenerative ability.

"We think that a major implication of this work is that there may be important drug targets in neurons that will allow us to enhance the rate of regeneration of these axons. We certainly hope it will be a pill - a small molecule to evade the blood-brain barrier. And it should also be small because we know the targets are within the cell," Barres concluded, "so it would have to be a membrane-permeable drug in any case."