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Spinal cord injury

spinal cord

Every year, about 2000 people in the UK, and several million people worldwide, suffer traumatic spinal cord injury leading to permanent paralysis. Average age at injury is 31, with the greatest frequency between 15 and 25 years. About four times as many have spinal cord lesions at birth or caused by disease. However,  according to a 2002 review article in The LancetANCHOR, "scepticism [about the prognosis] is giving way to the idea that spinal cord injury will eventually be reparable and that strategies to restore function are within our grasp."

The initial trauma includes both traction, which pulls nerve cells apart, and compression, which damages nerves and blood vessels. Nerve fibres that are detached from their cell nucleus must be rejoined within 48–72 hours or function is lost forever. The spinal cord swells within minutes, and there is further loss of blood supply when the pressure in the spinal canal rises. Lack of blood to the injured tissues, chemicals from disrupted nerve membranes, and electrolyte shifts trigger a cascade of secondary injuries that harm or kill neighbouring cells. Finally, scar tissues fills the void.

Most basic research in spinal injury is done on rats. However spinal injury is common in dogs, particularly dachshunds, and many dog owners are glad to let research be performed on their pets, which would otherwise have to be put down. Researchers at Cambridge University in the UKANCHOR, and at Purdue University in the USAANCHOR, in collaboration with local vets, are treating pet dogs with increasing success. Human clinical trials arising from dog results started at Purdue in 2004.

Promoting regrowth
Inhibition of scarring
Inhibiting the immune response
Implants and transplants
Combination therapies
References

Promoting regrowth

Researchers have discovered that rats with incomplete severance of the spinal cord have some capacity for regrowing fibres. When 3% of the forepaw connections remain, rats gradually recovered co-ordinated movements. Study of their spinal cords under the microscope showed spontaneous sprouting from nerve fibres spared by the original injury. This explains why some spontaneous motor recovery takes place after partial (40%) spinal cord injury, stroke and head trauma. The researchers are now testing whether sprouting can be promoted experimentally, by delivering nerve growth factors - proteins that stimulate nerve growth - to the injury siteANCHOR.

In 2003, scientists performed a meticulous series of experiments with rats, showing for the first time the presence of a signalling system called Wnt/frazzled that directs regrowing neurons to the right place after spinal injuryANCHOR.

Other naturally-occurring chemicals can help regenerating nerves to re-enter the spinal cordANCHOR ANCHOR ANCHOR ANCHOR. In embryos, the signalling protein named WNT-3 directs specific motor nerve cells to the correct connections in the spine, and this might be harnessed to aid recovery in injured adult animalsANCHOR.

An attractively simple approach to treating partial spinal injury is to inject a common antibiotic, minocycline, within one hour of injury. It reduces tissue loss by blocking release of a protein called cytochrome cANCHOR.

Inhibition of scarring

An important factor that inhibits recovery is the scarring that takes place after injury. When a barrier stopped inflammatory cells from reaching the injured site, nerve cells on both sides of the injury site were able to grow and re-establish connections with each other over two to three weeks, leading to substantial recovery of functionANCHOR. A compound that stops the growth of new blood vessels has also enabled mice with spinal cord injuries to walk againANCHOR, presumably by reducing scarring. A naturally occurring anti-inflammatory and anti-scarring agent, decorin, allowed nerve fibres to grow across nerve injuries in four daysANCHOR.

Inhibiting the immune response

Implanting specially treated immune system cells has also been successfulANCHOR. The signals produced by these cells may have been the reason that other researchers were able to get severed spinal nerves in rats to regrow into an beyond the site of the injuryANCHOR.

The immune system's involvement is complex: scientists have now shown in both rats and mice that central nervous system damage triggers an autoimmune reaction that actually protects nerve cells from further damage. This finding may lead to a vaccine to improve recovery following spinal cord injury and inhibit the cascade of damage that occurs after the initial traumaANCHOR. Rats vaccinated with protein fragments from the central nervous system soon after partial injury to the spinal cord showed significant recovery of movement and more healthy nerve fibres in the spinal cord than untreated ratsANCHOR.

Implants and transplants

Nerve transplants, usually from rat fetuses, have been shown to bridge spinal cord gaps in adult ratsANCHOR ANCHOR ANCHOR ANCHOR. Nerve tumour cells are particularly effective and allow rats to walk againANCHOR. In 2004 scientists successfully made an artificial framework of proteins that encourage regrowth, and these enabled nerve stem cells to regrow in a test tube. They then found that they could make the framework by injecting the proteins directly into the site of a spinal cord injury in a ratANCHOR.

Implants of embryonic stem cells, which have the ability to develop into any cell type in the body, might be successful. Nerve stem cells have been shown in mice to develop into all types of functioning nerve cellANCHOR. When mouse stem cells are transplanted into the damaged spinal cords of rats, the rats were able to walk againANCHOR.

Human stem cells injected into the spinal cord of paralysed rats became astrocyes (support cells) and sensory cells, but about four cells per rat became motor nerve cells that controlled movement, and had the unexpected additional effect of helping the rat nerve cells regrowANCHOR.

In 2004, scientists reported that they had isolated adult nerve cells and had cultured them two years in a test tube (the longest anyone has kept these self-renewing cells) and injected them into damaged spinal cord of rats, where they replaced missing cells. A reassuring finding was the lack of tumour growthANCHOR.

In 2003 scientists discovered that brain stem cells, unlike adult brain cells, are immune privileged, which means they can be transplanted into any part of the body without being rejectedANCHOR. In 2004 in a highly-sophisticated experiment, nerve stem cells were started on their development into motor neurons in a test tube and implanted into the spinal cords of injured rats, which were then treated with chemicals that prevented the nerve sheath cells from blocking development. Each rat received about 12,000 neurons, of which about 80 became fully-fledged motor nerve cells that were electrically linked with the spinal cordANCHOR.

Combination therapies

Scientists have achieved substantial success using a combination of nerve growth factor and antibodies that neutralise nerve growth inhibitorsANCHOR. Researchers also used genetically modified mice to produce two key proteins that, together, activated nerve growth in the spinal cord of adult mice. The ultimate step is to see if these work in spinal-injury patients, perhaps combined with therapies that neutralise nerve growth inhibitorsANCHOR. Another team of scientists achieved dramatic regrowth of axons using pre-treatment with cAMP, a tissue bridge of bone marrow cells, and nerve growth factorsANCHOR.

When rib nerves were grafted into the spinal cords of spinal-injured rats, accompanied with a growth factor called aFGF and physical stimulation, hind leg movement was partially restoredANCHOR.

Yet more work is required, but, as The Lancet pointed out, these promising results in rodents hold out the hope that we may soon be able to help human victims of spinal cord damage overcome their paralysis.

October 2004


References

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