Regular articleReducing inflammation decreases secondary degeneration and functional deficit after spinal cord injury
Introduction
Secondary degeneration defines a cascade of chemical and physiological events that are initiated by an original insult to the central nervous system (CNS), that lead to progressive tissue loss and cystic cavitation evolving away from the initial trauma site (Schwab and Bartholdi, 1996). Primary tissue damage initiated by mechanical trauma is at present irreversible, whereas secondary degeneration is amenable to pharmacological treatment. For example, high dose methylprednisolone has been shown to have some effect on the outcome of CNS trauma in clinical trials, and is believed to act by inhibition of lipid peroxidation (Hall, 2001). 4-Aminopyridine, a potassium channel blocker that helps demyelinated axons conduct, is currently in clinical testing (Nashmi and Fehlings, 2001). However, neither of these agents prevents the complicated pathological cascade triggered by spinal cord injury, and the efficacy of methylprednisolone, currently the standard of care for spinal cord injured patients, has been questioned (Hurlbert, 2000).
The immune system likely plays a critical role in the secondary degenerative process 2, 7, 30. Inflammation is triggered by injury, and precedes progressive tissue loss and cystic cavitation. The inflammatory response is typified by the influx of neutrophils, T lymphocytes, and macrophages, which have been shown to produce neurotoxic compounds under certain conditions 12, 25. The initial phase of the immune response involving leukocyte invasion is thought to be especially destructive, and is preceded by the expression of specific leukocyte chemoattractants including chemokines (McTigue et al., 1998). Chemokines are small pleiotropic cytokines that target defined populations of leukocytes during periods of inflammation.
Recent studies indicate that chemokines are expressed within the CNS following injury and that these molecules contribute to neuroinflammation 26, 11. Among the chemokines expressed during inflammatory neurologic disease is the T-lymphocyte chemoattractant chemokine CXCL10/IP-10 (interferon inducible protein 10 kDa) 26, 23. Recent studies have indicated an important role for this chemokine in triggering T-lymphocyte infiltration in the CNS during disease progression in animal models of the human demyelinating disease multiple sclerosis 23, 8. However, the contributions of this chemokine to T-lymphocyte trafficking and pathogenesis following CNS trauma is unknown.
To assess the contributions of CXCL10 and T cells to secondary degeneration following CNS trauma, spinal cord injured mice were treated with a neutralizing antibody specific for CXCL10 and the severity of histologic damage and behavioral impairment were determined. Neutralization of CXCL10 resulted in a dramatic reduction of secondary tissue loss and locomotor deficit, illustrating the functional significance of CXCL10 during spinal cord injury. These studies illustrate the feasibility of therapies designed to target chemokines, to reduce secondary degeneration and improve functional outcome following spinal cord injury.
Section snippets
Antibody administration
Age-matched adult female C57/BL6 mice received intraperitoneal injections of 100 μg of polyclonal CXCL10 antibody suspended in 500 μl of sterile phosphate-buffered saline (PBS) 1 day prior to injury, to assure systemic circulation of the antibodies and their immediate access to the antigen following injury. Treatment was continued every other day thereafter until day 9. Animals receiving the antibody treatment were chosen at random from the total animal group, and all subsequent animal and
Results
Ribonuclease protection assays of CXCL10 mRNA transcripts revealed dramatic increases in expression following hemisection injury. Whereas CXCL10 mRNA was not detectable in uninjured spinal cords, levels of expression increased by 6 h after a hemisection injury and then gradually declined, remaining elevated even after 14 days post injury (Fig. 1). The time course of increased CXCL10 expression is consistent with the hypothesis that CXCL10 plays a role in recruiting lymphocytes to the sites of
Discussion
Mechanical injury to the adult mammalian spinal cord results in an increase in vascular permeability, and a widespread activation and recruitment of inflammatory cells 5, 33. The control and consequences of this robust inflammatory response are largely unknown. A greater understanding of neuroimmune interactions can be seen in the field of multiple sclerosis research, where it has recently been demonstrated that attenuation of the T-lymphocyte response to demyelinating pathology in a viral
Acknowledgements
We thank Oswald Steward, Gabriel Nistor, and Giovanna Bernal for discussion and advice. We thank Josh Kunellis, Charlie Mendoza, and Julio Espinosa for assistance with animal care. This project was supported by the Roman Reed Spinal Cord Injury Research Fund of California, Research for Cure, and individual donations to the Reeve-Irvine Research Center.
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