Inosine regulates nerve cell growth

Boston area researchers think they've found the "master switch"

Researchers at Children's Hospital in Boston believe they have found the molecular mechanism that controls nerve cell regeneration, and the simple purine molecule inosine, seems to be at its center.

Normally, central nervous system (CNS) cells are unable to re-grow damaged fibers. Consequently, when such disruption occurs, their communication with other nerve cells is lost, causing debilitating losses in function for victims of stroke or traumatic injury. Previously, a group led by Larry Benowitz, director of the Laboratories for Neuroscience Research in Neurosurgery at Children's Hospital, reported that Inosine, a naturally occurring purine normally found in low levels in the brain, can promote extensive axon sprouting in animals with spinal cord injury.

Benowitz said: "What we have been trying to do since then is to understand what was happening on a molecular level. How does inosine do it?"

In the current paper, Benowitz and colleagues from the University of Konstanz (Konstanz, Germany) and the University of Michigan (Ann Arbor) describe the mechanism by which Inosine apparently works. The researchers describe a purine sensitive pathway that regulates axonal regrowth in retinal ganglion cells (RGC). The researchers found that inosine stimulated outgrowth and the characteristic pattern of molecular changes in RGCs (increased expression of certain cell surface proteins and the expression of a tubulin gene) and competitively reversed the inhibitory effects of 6-thioguanine, an inosine analog. In the adult brain, this cellular program is normally silent, and nerve cells that have been injured (e.g. by stroke) are not able to regenerate their axons.

Nevertheless, as described in this paper, this genetic program can be reactivated by Inosine. Benowitz's group is close to isolating the actual gene that encodes the enzyme upon which Inosine works. This, in turn, will enable them to gain further valuable and clinically relevant insights into the possibilities for regenerative axon growth in nerve cells.

"We knew from previous studies that there is a whole set of genes that are commonly activated only when nerve cells are forming their connections. However, we didn't know whether the expression of these genes was controlled through separate pathways that are activated by different growth factors, or whether there was a 'master switch,' onto which different signals converge to control the entire molecular program for axon growth. Our findings indicate that the regenerative effects of growth factors are mediated through this final common pathway," Benowitz added.

Benowitz and his group hope that by activating neurons with Inosine (as demonstrated in previous in vivo animal studies), they may be able to achieve regenerative axon growth in humans whose central nervous systems have sustained injury in stroke and spinal cord trauma.

This work was sponsored in part by Boston Life Sciences Inc., which is the exclusive commercial licensee of this technology for all therapeutic indications including spinal cord injury, stroke, and glaucoma.

"We hope to have inosine in the clinic sometime next year for the treatment of stroke and other CNS disorders," said Marc Lanser, chief scientific officer of BLSI.

Edited by Laura DeFrancesco
Managing Editor, Bioresearch Online
Email: ldefrancesco@bioresearchonline.com