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Beyond Animal Research

By Kristie Sullivan, M.P.H.
May 2005

Spinal Cord Injury Experiments on Animals

Every year, approximately 10,000 people in the United States suffer some sort of spinal cord injury; many thereafter are confined to wheelchairs and forced to adapt to a host of medical challenges.1 Decreased activity can lead to bone and muscle loss, weight gain, cardiovascular disease, diabetes mellitus, and circulatory dysfunction. Others experience idiopathic pain sensations, muscle spasticity, and pressure ulcers on the skin. Finally, most have functional difficulties with the digestive, excretory, and reproductive systems.

Unfortunately, the tragic results of spinal cord injuries (SCI) are in fact two-fold. In an effort to help people with SCI, many researchers are attempting to create animal “models” of injured humans. Over the past few decades, much effort and expense has been spent creating sophisticated impaction devices and other injury techniques designed to eliminate variability and deliver a reproducible spinally injured animal. Every year, thousands of animals are given spinal cord injuries through blunt trauma, loss of blood flow, or surgical transection, then treated or dissected in hopes that a cure will be found.

Some of these projects have seemed to bear fruit—at first. Scientists have managed to re-grow damaged neural tissue in the spinal cords of rats,2-4 see cats with completely cut spinal cords walk again, determine detailed information about neural connectivity in macaques,5 and prevent secondary damage to neural tissue after injury.6 Thousands of animals have been injured and evaluated.

Unfortunately, and perhaps predictably, not one of these experiments has actually led to a cure or effective treatment for human spinal cord injury. Out of nearly two dozen therapies suggested to be effective in non-human animals,7 only one (methylprednisolone) proved helpful to injured humans.8 Even the effectiveness of methylprednisolone is now being called into serious question by practicing clinicians.

Perhaps the most salient reasons for this failure are related to anatomy—each species has a unique spinal orientation, movement kinetics, and neural anatomy. Furthermore, every human spinal injury comes with its own set of physical, neurochemical, and histological pathologies that cannot be properly duplicated in a laboratory setting.

On the other hand, human research methods have produced promising results, and others are worth a closer look. Here’s a sampling:

  • A group of London researchers found that damage to spinal cord neurons in cell culture was prevented by inhibiting a specific nuclear enzyme apparently involved in peroxynitrite-induced cell damage after injury.9
  • A procedure to create human motoneuron cell lines in culture was developed in 2000.10 Researchers found the cloned neurons displayed normal neuronal processes, including immunoreactivity and action potential firing, and researchers were also able to coax clonal precursor cells into multiple types of spinal cord neurons.10
  • Non-invasive imaging techniques, such as PET, SPECT, and fMRI, as well as more invasive cerebrospinal fluid studies, can be used to visualize neural pathology at various time points after injury and monitor the effects of experimental therapies. By studying neuromuscular connections in both uninjured and spinal cord-injured patients, University of Miami School of Medicine scientists have found mechanisms in the spinal cord that are responsible for coordinating opposing muscle movements.11
  • In Miami, researchers are collaborating on the Human Spinal Cord Injury Model project. This project is studying spinal cord injured patients, both pre- and post-mortem, to build a more realistic understanding of human spinal cord injury. Post-mortem spinal cord tissue can be compared to MRIs to determine histopathological changes in cells and tissues.12,13

Researchers, clinicians, and patients alike agree that a more directed effort to establish human clinical research projects is needed. While success in restoring functional endpoints has been realized in a number of areas,14-23 more investment in this avenue of research is needed. Only then will true success be realized.

Kristie Sullivan, M.P.H., is a PCRM research analyst.

References
1. Reyes O, Sosa I, Kuffler DP Neuroprotection of spinal neurons against blunt trauma and ischemia. P R Health Sci J. 2003;22(3):277-286.
2. Li Y and Raisman G. Schwann cells induce sprouting in motor and sensory axons in the adult rat spinal cord. J Neurosci. 1994;14:4050-4063.
3. Richardson PM, Issa VMK, Aguayo AJ. Regeneration of long spinal axons in the rat. J Neurocytology. 1984;13:165-182.
4. Li WWY, Yew DTW, Chuah MI, Leung PC, Tsang DSC. Axonal sprouting in the hemisected adult rat spinal cord. Neurosci. 1994;61(1):133-139.
5. Galea MP and Darian-Smith I. Multiple corticospinal neuron populations in the macaque monkey are specified by their unique cortical origins, spinal terminations, and connections. Cereb Cortex. 1994;4:166-194.
6. Yu CG, Jimenez O, Marcillo AE, Weider B, Bangerter K, Dietrich WD, Castro S, Yezierski RP. Beneficial effects of modest systemic hypothermia on locomotor function and histopathological damage following contusion-induced spinal cord injury in rats. J Neurosurg. 2000;93(1 Suppl):85-93.
7. Maiman D. Symposium on spinal cord injury models: Introduction. J Am Paraplegia Soc. 1988;11:23-25.
8. Dobkin BH and Havton LA. Basic advances and new avenues in therapy of spinal cord injury. Annu Rev Med. 2004;55:255-282.
9. Scott GS, C Szabo, DC Hooper. Poly(ADP-ribose) polymerase activity contributes to peroxynitrite induced spinal cord neuronal cell death in vitro. J Neurotrauma. 2004;21(9):1255-1263
10. Li R, S Thode, N Richard, J Pardinas, MS Rao, DW Sah. Motoneuron differentiation of immortalized human spinal cord cell lines. J Neurosci Res. 2000;59(3):342-352.
11. Perez MA, EC Field-Fote. Impaired posture-dependent modulation of disynaptic reciprocal Ia inhibition in individuals with incomplete spinal cord injury. Neurosci Lett. 2003;341(3):225-228.
12. Emery E, P Aldana, MB Bunge, W Puckett, A Srinivasan, RW Keane, J Bethea, AD Levi. Apoptosis after traumatic human spinal cord injury. J Neurosurg. 1998; 89(6):911-920.
13. Bruce JH, MD Norenberg, S Kraydieh, W Puckett, A Marcillo, D Dietrich. Schwannosis: role of gliosis and proteoglycan in human spinal cord injury. J Neurotrauma. 2000;17(9):781-788.
14. Herman, R, J He, S D’Luzansky, W Willis, S. Dilli. Spinal cord stimulation facilitates functional walking in a chronic incomplete spinal cord injured. Spinal Cord. 2002;40(2):65-68.
15. Carhart MR, J He, R Herman, S D’Luzansky, WT Willis. Epidural spinal-cord stimulation facilitates recovery of function walking following incomplete spinal-cord injury. IEEE Trans Neural Syst Rehabil Eng. 2004;12(1):32-42.
16. Widerstrom-Noga EG and DC Turk. Types and effectiveness of treatments used by people with chronic pain associated with spinal cord injuries: influence of pain and psychosocial characteristics. Spinal Cord. 2003;41(11):600-609.
17. Nance PW, J Bugaresti, K Shellenberger, W Sheremata, A Martinez-Arizala. Efficacy and safety of tizanidine in the treatment of spasticity in patients with spinal cord injury. North American tizandine study group. Neurology. 1994;44(11 Suppl 9):S44-951.
18. Mathew KM, G Ravichandran, K May, K Morsley. The biophyschosocial model and spinal cord injury. Spinal Cord. 2001;39(12):644-649.
19. Raghavan P, WA Raza, YS Ahmed, MA Chamberlain. Prevalence of pressure sores in a community sample of spinal injury patients. Clin Rehabil. 2003;17(8):879-884.
20. Sprigle S, M Linden, D McKenna, K Davis, B Riordan. Clinical skin temperature measurement to predict incipient pressure ulcers. Adv Skin Wound Care. 2001;14(3):133-137.
21. Moussavi RM, HM Garza, SG Eisele, G Rodriguez, DH Rintala. Serum levels of vitamins A, C, and E in persons with chronic spinal cord injury living in the community. Arch Phys Med Rehabil. 2003;84(7):1061-1067.
22. Korsten MA, NR Fajardo, AS Rosman, GH Creasey, AM Spungen, WA Bauman. Difficulty with evacuation after spinal cord injury: Colonic motility during sleep and effects of abdominal wall stimulation. J Rehabil Res Dev. 2004;41(1):95-100.
23. Creasey GH, JH Grill, M Korsten, U HS, R Betz, R Anderson, J Walter, Implanted Neuroprosthesis Research group. An implantable neuroprosthesis for restoring bladder and bowel control to patients with spinal cord injuries: a multicenter trial. Arch Phys Med Rehabil. 2001;82(11):1512-1519.

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