Review
Degenerative and regenerative mechanisms governing spinal cord injury

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Abstract

Spinal cord injury (SCI) is a major cause of disability, and at present, there is no universally accepted treatment. The functional decline following SCI is contributed to both direct mechanical injury and secondary pathophysiological mechanisms that are induced by the initial trauma. These mechanisms initially involve widespread haemorrhage at the site of injury and necrosis of central nervous system (CNS) cellular components. At later stages of injury, the cord is observed to display reactive gliosis. The actions of astrocytes as well as numerous other cells in this response create an environment that is highly nonpermissive to axonal regrowth. Also manifesting important effects is the immune system. The early recruitment of neutrophils and at later stages, macrophages to the site of insult cause exacerbation of injury. However, at more chronic stages, macrophages and recruited T helper cells may potentially be helpful by providing trophic support for neuronal and non-neuronal components of the injured CNS. Within this sea of injurious mechanisms, the oligodendrocytes appear to be highly vulnerable. At chronic stages of SCI, a large number of oligodendrocytes undergo apoptosis at sites that are distant to the vicinity of primary injury. This leads to denudement of axons and deterioration of their conductive abilities, which adds significantly to functional decline. By indulging into the molecular mechanisms that cause oligodendrocyte apoptosis and identifying potential targets for therapeutic intervention, the prevention of this apoptotic wave will be of tremendous value to individuals living with SCI.

Introduction

Spinal cord injury (SCI) occurs in most countries at an annual rate of 20–40 persons per million (Tator and Fehlings, 1991). In the United States, this sums up to approximately 10,000 new cases a year, which continuously adds to the nation's estimated 200,000 quadriplegics Ropper, 2001, Tyor et al., 2002. The main causes of trauma to the cord are motor-vehicle accidents, sports and recreational activities, work-related accidents and falls at home. More importantly, the majority of SCI victims are young and otherwise healthy, who in addition to costing society up to $200,000 each per year, suffer the impingement of life long disability (Tyor et al., 2002). At present, there is no universally accepted treatment for this condition (Beattie et al., 2002b).

The greater part of spinal cord injuries in civilian life arise from fracture or dislocation of the vertebral column. Most commonly this arises due to compression with flexion in the thoracic cord and hyperextension or flexion in the cervical cord. Indicators increasing the risk of SCI as a result of minimal trauma are preexisting spondylosis, a congenital spinal canal stenosis, hypertrophied ligamentum flavum and instability of apophyseal joints due to rheumatoid arthritis (Ropper, 2001).

Manifestation of SCI has varying degrees and is wholly dependent on the severity and level of injury to the cord. The rule of thumb is that the higher the level of the lesion, the more severe the consequences. In the case of high cervical injury, patients require artificial respiration to stay alive. This type of injury also leads to tetraplegia, impairment of function in pelvic organs and loss in motor and sensory function of the arms, trunk and legs. Injury to lower cord levels, depending again on the exact level, may leave function in the upper limbs with impairment limited to lower limbs. This phenomenon of paraplegia is restricted to injuries of the thoracic or lumbar cord Maynard et al., 1997, Ropper, 2001.

Section snippets

Neuropathology of SCI

The pathological sequelae following acute SCI are divided into two broad chronological events: the primary injury and the secondary injury (Tator and Fehlings, 1991). The primary injury encompasses the focal destruction of neural tissue caused by direct mechanical trauma. This initial insult then instigates a progressive wave of secondary injury, which via the activation of a barrage of noxious pathophysiological mechanisms exacerbates the injury to the spinal cord. As this leads to the

The immune system in SCI

Inflammatory responses are of central importance in the pathogenesis of the acute and chronic phases of SCI. During these phases, the CNS recruits both the innate and adaptive arms of immunity (Hauben and Schwartz, 2003).

Molecular mechanisms in SCI

The complex pathophysiology of SCI leads to activation as well as inhibition of numerous molecular mechanisms involved in secondary injury. The following paragraphs will deal with mechanisms more specific to oligodendrocytes and the precedence for administering leukaemia inhibitory factor (LIF) as a possible therapeutic measure.

Acknowledgements

This study was supported by the National Health and Medical Research Council of Australia Program Grant and the Trish-MS Research Foundation.

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