Nerve Grafting for Spinal Cord Injury in Cats: Are We Close to Translational Research?
Hanna, Amgad S; Côté, Marie-Pascale; Houlé, John; Dempsey, Robert
In a recent paper (Peripheral nerve grafts after cervical spinal cord injury in adult cats) published in Experimental Neurology, Houlé et al are one step closer to translational research in spinal cord injury (SCI). They moved from a rat model to a cat model, which is closer in anatomy to the human spinal cord.1 Little progress has been made to help recovery after SCI. A key inhibitor to regeneration after SCI is the presence of chondroitin sulfate proteoglycans (CSPG).2 Neutralizing CSPGs after SCI has been shown to enhance axonal regeneration3 and improve functional recovery in rats4 and cats.5
Twelve adult female cats received a lower cervical (C7) partial hemisection lesion with acute apposition of a segment of autologous tibial nerve to the lesion site. This was a pre-degenerated nerve, cut proximally a week before. Five weeks later a dorsal quadrant lesion was made at T1, the lesion site was treated with ChABC to digest growth inhibiting extracellular matrix molecules and the distal end of the PNG was apposed to the fresh injury site (Figure 1). To assess the extent of axon growth into and out of the graft, tract staining was performed 4 to 6 weeks later; the graft was transected and the proximal end stained with True Blue (TB), while the distal end was stained with fluorescein dextran (Fluoro-Emerald, FE). Electrophysiological experiments were used to evaluate the conduction of action potentials through the graft. Graft stimulation and recording was performed through a hook electrode. Spinal cord stimulation was delivered with a single platinum iridium electrode, while recording was through a 16 channel electrode. Grafts survived in 10 of 12 animals, with a mean of 2476 ± 1254 (range, 1343-4234) myelinated axons per graft. The distal end of each graft was well apposed to the spinal cord and numerous axons extended beyond the graft back into the cord (Figure 2). Axon conduction through the graft was established by stimulating the spinal cord rostral to the graft and recording from the graft surface. Electrical stimulation of the graft in this animal failed to elicit detectable electromyographic (EMG) signals in the affected forelimb however immunocytochemical reaction demonstrated the presence of c-Fos positive spinal cord neurons close to the distal apposition site (Figure 3), indicating synaptic activation through regenerated axons. In another animal, stimulation of the graft elicited EMG responses in the triceps muscle through antidromic activation of axons that had grown into the graft. These results indicate the successful placement of a PNG in the cat spinal cord and the ability to identify anatomical regeneration and to measure physiological activity within the grafts.
The spinal cord deprived of descending influence from the brain has been a popular and productive experimental model for more than a century. The cat's size allows for a detailed testing of PN grafting strategy in a SCI model closer in size to humans; the mean length of the feline spinal cord is 34 cm vs 40 to 45 cm in humans.6 The current paper revealed establishment of a good anatomical bridge using PNG in an incomplete SCI model in cats. Axonal growth was enhanced using ChABC. The severity of injury was not sufficient to study clinical improvement. The results could be maximized using other modalities to enhance axonal regeneration. Studies revealed the effectiveness of a step-training program in the adult cat to promote treadmill walking after SCI.7 Recovery of function after SCI will most likely result from a combination approach involving regeneration, neuroprotection, neurotrophic factors, neutralization of inhibitory molecules, rehabilitation and/or electrical stimulation of muscles and spinal networks. The efficacy of treatments in large animal models will best provide preclinical evidence that is necessary before moving forward with human SCI trials.8
Amgad S. Hanna
1. Cote MP, Hanna A, Lemay MA, et al. Peripheral nerve grafts after cervical spinal cord injury in adult cats. Exp Neurol. 2010;225(1):173-182.
2. Busch SA, Silver J. The role of extracellular matrix in CNS regeneration. Curr Opin Neurobiol. 2007;17(1):120-127.
3. Massey JM, Amps J, Viapiano MS, et al. Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3. Exp Neurol. 2008;209(2):426-445.
4. Caggiano AO, Zimber MP, Ganguly A, Blight AR, Gruskin EA. Chondroitinase ABCI improves locomotion and bladder function following contusion injury of the rat spinal cord. J Neurotrauma. 2005;22(2):226-239.
5. Tester NJ, Howland DR. Chondroitinase ABC improves basic and skilled locomotion in spinal cord injured cats. Exp Neurol. 2008;209(2):483-496.
6. Perese DM, Fracasso JE. Anatomical considerations in surgery of the spinal cord: a study of vessels and measurements of the cord. J Neurosurg. 1959;16(3):314-325.
7. Rossignol S, Chau C, Brustein E, Belanger M, Barbeau H, Drew T. Locomotor capacities after complete and partial lesions of the spinal cord. Acta Neurobiol Exp (Wars). 1996;56(1):449-463.
8. Kwon BK, Hillyer J, Tetzlaff W. Translational research in spinal cord injury: a survey of opinion from the SCI community. J Neurotrauma. 2010;27(1):21-33.
Copyright © by the Congress of Neurological Surgeons