Spinal cord injury
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 Lancet
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 UK , and at Purdue University in the USA , in collaboration with local vets, are treating pet dogs with increasing success. Human clinical trials arising from dog results started at Purdue in 2004.
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 site
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 injury .
Other naturally-occurring chemicals can help regenerating nerves to re-enter the spinal cord . 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 animals .
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 c .
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 function. A compound that stops the growth of new blood vessels has also enabled mice with spinal cord injuries to walk again , presumably by reducing scarring. A naturally occurring anti-inflammatory and anti-scarring agent, decorin, allowed nerve fibres to grow across nerve injuries in four days .
Implanting specially treated immune system cells has also been successful
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 trauma . 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 rats .
Nerve transplants, usually from rat fetuses, have been shown to bridge spinal cord gaps in adult rats
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 cell . When mouse stem cells are transplanted into the damaged spinal cords of rats, the rats were able to walk again .
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 regrow .
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 growth .
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 rejected . 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 cord .
Scientists have achieved substantial success using a combination of nerve growth factor and antibodies that neutralise nerve growth inhibitors
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 restored .
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.
- McDonald JW, Sadowsky C (2002) Spinal cord injury. Lancet 359, 417.
- RDS News, January 2001, p.10.
- See http://www.vet.purdue.edu/cpr/
- Weidner N, Ner A, Salimi N & Tuszynski MH (2001) Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury Proc Nat Acad Sci 98, 3513.
- Lyuksyutova AL, Lu C-C, Milanesio N (2003) Anterior-posterior guidance of commissural axons by Wnt-Frizzled signaling. Science 302, 1984.
- Ramer MS, Priestley JV, & McMahon SB (2000) Functional regeneration of sensory axons into the adult spinal cord Nature 403, 312.
- Grandpré T, Li S & Strittmatter (2002) Nogo-66 receptor antagonist peptide promotes axonal regeneration Nature Neuroscience 417, 547.
- Neumann S, Bradke F, Tessier-Lavigne M & Basbaum A (2002) Regeneration of sensory axons within the injured spinal cord induced by intraganglionic camp elevation Neuron 34, 885.
- Qui J, Cai, D, Dai H et al (2002) Spinal axon regeneration induced by elevation of cyclic AMP Neuron 34, 895.
- Krylova O, Herreros J, Cleverley KE et al (2002) WNT-3, expressed by motoneurons, regulates terminal arborization of neurotrophin-3-responsive spinal sensory neurons Neuron 35, 1043.
- Teng YD, Choi H, Onario RC et al (2004) Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury. Proc Nat Acad Sci 101, 3071.
- Seitz A, Aglow E, Heber-Katz E (2002) Recovery from spinal cord injury: A new transection model in the C57Bl/6 mouse J Neurosci Res 67, 337.
- Wamil AW, Wamil BD, Hellerqvist CG (1998) CM101-mediated recovery of walking ability in adult mice paralyzed by spinal cord injury Proc Nat Acad Sci 95, 13188.
- Davies JE, Tang X, Denning JW et al (2004) Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes axon growth across adult rat spinal cord injuries. Eur J Neurosci 19, 1226.
- Rapalino O, Lazarov-Spiegler O, Agranov E et al (1998) Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nature Medicine 4, 814.
- Neumann S & Woolf CJ (1999) Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury Neuron 22, 83.
- Yoles E, Hauben E, Palgi O et al (2001) Protective autoimmunity is a physiological response to CNS trauma J Neurosci 21, 3740.
- Hauben E, Agranov E, Gothilf A et al (2001) Post traumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease J Clin Invest 108, 108.
- Iwashita Y Kawaguchi S & Murata M (1994) Restoration of function of spinal cord segments in the rat Nature 367, 167.
- Cheng H, Cao Y, Olson L (1996) Spinal cord repair in adult paraplegic rats: Partial restoration of hind limb function Science 273, 510.
- Davies SJA, Fitch MT, Memberg SP et al (1997) Regeneration of adult axons in white matter tracts of the central nervous system Nature 390, 680.
- Imaizumi T, Lankford KL, Burton WV et al (2001) Xenotransplantation of transgenic pig olfactory ensheathing cells promotes axonal egeneration in rat spinal cord Nature Biotech, 18, 949.
- Saporta S, Makoui AS, Willing A et al (2002) Functional recovery after complete contusion injury to the spinal cord and transplantation of human neuroteratocarcinoma neurons in rats J Neurosurg: Spine 97, 63.
- Silva GA, Czeisler C, Niece KL et al (2004) Selective differentiation of neural progenitor cells by high-epitope density nanofibers. Science 303, 1352.
- Flax JD, Aurora S, Yang C et al (1998) Engraftable human neural stem cells respond to development clues, replace neurons, and express foreign genes Nature Biotechnology 16, 1033.
- McDonald J, Liu X.Z, Qu Y et al (1999) Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord Nature Med 5, 1410.
- Kerr DA, Lladó J, Shamblott MJ et al (2003). Human embryonic germ cell derivatives facilitate motor recovery of rats with diffuse motor neuron injury. J Neurosci 23, 5131.
- Roy NS, Nakano T, Keyoung HM et al (2004) Telomerase immortalization of neuronally restricted progenitor cells derived from the human fetal spinal cord. Nature Biotechnology 22, 297.
- Hori J, Ng TF, Shatos M et al (2003) Neural progenitor cells lack immunogenicity and resist destruction as allografts. Stem Cells 21, 405.
- Harper JM, Krishnan C, Darman JS (2004) Axonal growth of embryonic stem cell-derived motoneurons in vitro and in motoneuron-injured adult rats Proc Nat Acad Sci 101, 7123.
- Schnell L, Schneider R, Kolbeck R et al (1994) Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion Nature 367, 170.
- Bomze HM, Bulsara KR, Iskandar BJ et al (2001) Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons Nature Neurosci 4, 38.
- Lu P, Yang H, Jones LL, Filbin MT, Tuszynski MH (2004) Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. J. Neuroscience 24, 6402.
- Lee Y-S, Hsiao I, Lin VW (2002) Peripheral nerve grafts and aFGF restore partial hindlimb function in paraplegic rats. J Neurotrauma, 19, 1203.
Last edited: 5 November 2014 11:52