Elsevier

Progress in Neurobiology

Volume 78, Issue 2, February 2006, Pages 91-116
Progress in Neurobiology

Experimental strategies to promote spinal cord regeneration—an integrative perspective

https://doi.org/10.1016/j.pneurobio.2005.12.004Get rights and content

Abstract

Detailed pathophysiological findings of secondary damage phenomena after spinal cord injury (SCI) as well as the identification of inhibitory and neurotrophic proteins have yielded a plethora of experimental therapeutic approaches. Main targets are (i) to minimize secondary damage progression (neuroprotection), (ii) to foster axon conduction (neurorestoration) and (iii) to supply a permissive environment to promote axonal sprouting (neuroregenerative therapies). Pre-clinical studies have raised hope in functional recovery through the antagonism of growth inhibitors, application of growth factors, cell transplantation, and vaccination strategies. To date, even though based on successful pre-clinical animal studies, results of clinical trials are characterized by dampened effects attributable to difficulties in the study design (patient heterogeneity) and species differences. A combination of complementary therapeutic strategies might be considered pre-requisite for future synergistic approaches. Here, we line out pre-clinical interventions resulting in improved functional neurological outcome after spinal cord injury and track them on their intended way to bedside.

Section snippets

Epidemiology and clinic

Given an increasing incidence of spinal cord injury and an almost unaltered life time expectation, it has been estimated that 2.5 million spinal cord injured patients are living worldwide. In comparison to Europe the incidence of SCI in the US is higher, mainly due to gunshot wounds (DeVivo, 1997, McDonald, 1999, The National SCI Statistical Center, 2001). About 40% of the patients suffer from quadriplegia, 60% from paraplegia. In about 60% of the patients, the sensory and/or motor paralysis is

Pathophysiology—an update

Upon initial impact the vertebral fracture causes a local, segmental-limited damage of the spinal cord (primary damage, Fig. 1, Fig. 2). As a consequence of rupture or contusion of axons, hemorrhage, ischemia and edema develops. The damage considerably expands during the first weeks due to further destruction of neuronal and glial cells (secondary damage, Fig. 2) (Tator, 1995, Tator, 1998). First, the lesion expands vertically through the gray matter; and then spreads further horizontally

Neuronal and glial protection

To reduce the formation of cytotoxic edema, inflammation and the release of glutamate and free radicals (Fig. 2B and C) a high dose of methylprednisolone (30 mg/kg) can be administered during the early acute phase (<8 h). However, this treatment is still controversial (Short, 2000, Short et al., 2000, Hurlbert, 2001). In the United States this therapy is frequently applied. On the contrary, not all European centers are using methylprednisolone, since it leads to a higher rate of complications

Causes for the lack of substances with unquestionable clinical effectiveness

For several reasons it is difficult (see below) to transfer successful experimental results (Wickelgren, 2002) to the clinical situation (Pearson, 2003). In some aspects this due to species differences between rodents and human, for example, in the case of glial reactions upon spinal cord injury (Puckett et al., 1997, Norenberg et al., 2004, Kakulas, 2004). In addition, compensatory mechanisms upon SCI are more frequently observed in rodents compared to humans. On the clinical side problems in

Future prospects

The possibility to specifically direct the axonal growth towards the original deafferenting site is still in the distant future (McDonald and Sadowsky, 2002). The fact, however, that merely 10% of the original axons are necessary to achieve a significant functional improvement in rodents (Barnett et al., 2000, Blight, 1983) gives reason for hope, as well as the fact that an important part of the distal axon ends still remain at the lesion for a long time after the spinal cord injury (Hill et

Acknowledgements

This work is supported by the Wings for Life Spinal Cord Research Foundation. JMS was awarded by an international “poste rouge” scholarship of the Centre National de la Recherche Scientifique (CNRS), France and is at present a Research Fellow supported by the German Research Council (DFG), #1164/1-1. We would like to thank Dr. Kattie Luyten and Simone Mucha for their help in preparing the manuscript.

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