By David N. Leff

A person who can't tell left from right has only his cerebral cortex to blame.

"Our left cerebral hemisphere," observed neuroscientist Larry Benowitz, "controls the right side of our body; the right hemisphere, the left side. Two parallel independent tracts of axons, one on the left side, one on the right, run down the spinal cord. These two corticospinal tracts cross completely, so the one originating on the left hemisphere of the brain runs down the right side. The one originating on the right runs down the left side.

"Physically," Benowitz continued," both tracts course down from the motor cortex, the high-command center for movement, where the nerves' cell bodies are. These so-called pyramidal cells live up there in the motor cortex. They send their axons down through the brain stem, through the medulla oblongata, and then - just before they enter the spinal cord - the two tracts cross."

Benowitz directs the Laboratories for Neuroscience Research in Neurosurgery at Harvard-affiliated Children's Hospital in Boston. His brief lesson in spinal-cord Anatomy 101 relates to a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated Nov. 9, 1999, of which he is senior author. Its title: "Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury."

"Inosine is a small molecule occurring in most cells," Benowitz told BioWorld Today. "It's a purine nucleoside, indirectly related to DNA and RNA synthesis. Last year," he recounted, "growing nerve cells in tissue culture, we discovered that inosine has very potent effects in stimulating neurons to turn on a program of gene expression that will cause the brain cell to grow an axon."

This original in vitro finding led to the in vivo experiment he reported in PNAS - testing inosine's ability to repair a spinal-cord wound that interrupted commands between nerve cells in the cerebral cortex, down the length of the spine, to control lower limb movements in rats.

In humans, those axons carry signals from the cortex, via the corticospinal tract, to activate the muscles of fingers, hands, legs and feet, required for everyday movements such as writing, playing piano, walking.

Once Put Asunder, Never Rejoined?

In severing one of the rats' two axonal tracts, then dosing their cortex with inosine to restore the connections, Benowitz and his co-authors were challenging a long-standing dogma: "Axonal growth in the spinal cord," he pointed out, "has generally been viewed as a highly inhibitory terrain.

"The nerve fibers," he explained, "are ensheathed by myelin, put there by the brain's glial cells. That terrain is generally viewed as being strongly suppressive to axonal growth, which is part of the reason people believe that regenerative proliferation does not occur in the central nervous system, because it's inhibited by myelin.

"But somehow," Benowitz recalled, "with this stimulation of the neural program, using inosine, we were able to get the axons to revert to a growth state where they think they're kids again, and start doing again what they did back in their developmental youth, which was growing axonal branches.

"We performed unilateral hemi-transection on 14 rats," Benowitz recalled. "That is, we cut through their left corticospinal tract, just above the top of the spine."

A few hours later, using a minipump, the co-authors infused inosine directly into one side of the motor cortex in the animals' brains. This was the site of origin for those axons descending into the uninjured side of the corticospinal tract.

"The outcome of the study was that inosine had amazingly powerful effects on stimulating that kind of axon growth in the spinal cord," Benowitz recounted. "After 14 days, all but one of the treated animals showed signs of extensive collateral sprouting of axons from the uninjured to the injured side of the corticospinal tract - reaching below the level of hemi-transection. This axonal proliferation continued to descend down the injured side of the tract, replacing severed axons with new ones."

Along the tract, they sent off a new collateral branch that crossed over to the denervated side - the side that had lost its nerve connections. Then that new branch ran right down the white matter, the myelinated tract that had lost its normal axons. The number of new axons ranged up to 2,500 per treated rat, compared to 28 to 170 seen in control animals.

Test Of Function Comes Next

This first study of inosine in vivo was a proof of anatomical - not functional - principle, Benowitz pointed out. "The rats will have lost very fine control of their toes and fingers. In us humans, the pyramidal tract is really a big deal. In the rat it's important for fine motor control, fine movements of their four paws and digits. So in fact," he allowed, "behavior mediated by this tract is a little bit subtle in the rat. Nonetheless, the reason that we focus on it is because the analogous pathway in humans is so important.

"We have volunteer rats lined up outside, as it were," Benowitz added. "We've started doing the functional experiments now, and have just received support from the Christopher Reeve Paralysis Foundation, as well as a special NIH director's award to do this spinal cord study. Also, more financing from Boston Life Sciences Inc. [BLS], which partially funded this PNAS-reported work."

BLS has licensed, exclusively from Children's Hospital, the Benowitz patent to treat neurodegenerative disorders, both acute and chronic, with inosine.

"We're planning to bring it into the clinic for trials of stroke and spinal cord injury late next year, BLS' chief scientific officer, Marc Lanser, told BioWorld Today. "We want to see if we can administer inosine intravenously or even orally. And that will depend, obviously, on the percentage that crosses the blood-brain barrier, and the bioavailability for oral administration."