UNTREATABLE nerve damage caused by anything from a car accident to multiple sclerosis may be a thing of the past if a new family of compounds lives up to its discoverers鈥� expectations. So far, the drugs have shown promising results in animal tests and human trials could begin within two years.
Researchers at Guilford Pharmaceuticals of Baltimore, Maryland, have successfully used the compounds, called neuro-immunophilin ligands (NILs), to regenerate severely damaged nerve tissue in rats.
Guilford鈥檚 vice-president of research, Peter Suzdak, says: 鈥淭ake something like Parkinson鈥檚 disease鈥攖his could revolutionise the way it鈥檚 treated. These compounds will stop degeneration of nerve cells and promote the regeneration of nerve tissue. We鈥檙e extremely excited.鈥�
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Rats with crushed sciatic nerves鈥攖he large nerves that run down each back leg鈥攕how a 50 per cent decrease in the number of axons (the fibres that conduct an impulse away from a cell) and a 90 per cent drop in the amount of myelin sheath (the fatty cover around axons that helps the conduction of nerve impulses).
Using this model of nerve damage, the team found that one of their new chemicals, GPI 1005, caused the number of axons to regenerate to 95 per cent, and myelination to increase to 50 per cent鈥攅ven when administered at tiny concentrations.
Gordon Wilcock, professor of care of the elderly at Bristol University and chair of the Alzheimer鈥檚 Disease Society medical advisory panel, says: 鈥淭here鈥檚 no question these findings are potentially very important. The degree of regeneration really is quite dramatic.鈥�
But he notes that in some of the experiments, the Guilford researchers gave the chemicals to the rats not only to treat the crushed nerves, but also before the injury as a possible preventative measure. This would not be feasible in humans, because the onset of neurological diseases is unpredictable. In the case of Parkinson鈥檚 disease, for example, 70 per cent of dopaminergic neurons are damaged before symptoms appear.
These are not the first compounds found to stimulate nerve growth. Researchers have known for several years that immunosuppressant drugs such as cyclosporin A, FK506 and rapamycin can stimulate nerves to grow back following facial injuries. But these powerful drugs, used to prevent the rejection of transplanted organs, cause too much damage to the immune system to be used for the long-term treatment of neurological problems. Suzman says that NILs appear to stimulate nerve tissue growth in the same way that cyclosporin A and FK506 do, but without damaging the immune system.
The nerve growth promoting effect of the most promising NIL, known as GPI 1046, appears to come from its ability to block the cell membrane enzyme rotamase, which would normally dock on a receptor called FKBP 12. This sets off a cascade of chemical changes in the cell, which activates the growth-associated protein GAP43. This protein leaves the cell and promotes nerve tissue growth.
Immunosuppressant drugs have the same effect, but they also alter the overall amount of calcium in cells, and it is this which seems to hit the immune system. The NILs were designed to have no effect on total calcium levels.
However, Joseph Coyle, chairman of psychiatry at Harvard University and a member of Guilford鈥檚 scientific advisory board, is cautious: 鈥淚t鈥檚 a little early to say much about side effects. A significant number of very prominent drugs get thrown out because of unforeseen side effects.鈥�
Wilcock also warned that the new chemicals鈥� apparent ability to act against a wide range of nerve cells might backfire. 鈥淚f, for example, they鈥檙e being used to treat Parkinson鈥檚 disease, we need to know if they will have an effect on other, perfectly healthy, nerve tissues,鈥� he says.
