Abstract
Study design:
Assessment of the potential protective effects of inosine on an animal model of spinal cord injury.
Objectives:
Our previous studies have demonstrated that inosine can directly protect neurons in vitro from zinc-induced injury and axotomized retinal ganglion cells of rats in vivo. This investigation was carried out to examine the possible protective effects of inosine on spinal cord secondary degeneration.
Setting:
Institute of Neurosciences, The Fourth Military Medical University, Xi'an, China.
Methods:
Compressive spinal cord injury (95-g load for 1 min) model was established in rats, and inosine was administrated beginning at different time points (2, 12, or 24 h) after spinal cord injury.
Results:
Using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) technique and hematoxylin and eosin staining, our study demonstrated that administration of inosine as late as 12 h after injury significantly reduced the total volume of spinal cord degenerative areas and the number of apoptotic cells 3 days following the trauma.
Conclusion:
Inosine can significantly reduce the spread of secondary degeneration and the cell death following spinal cord injury in adult rats. These findings may find a clinical application in the treatment of acute spinal cord injury.
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References
Tator CH, Fehlings MG . Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg 1991; 75: 15–26.
Schwab ME, Bartholdi D . Degeneration and regeneration of axons in the lesioned spinal cord. Physiol Rev 1996; 76: 319–370.
Amar AP, Levy ML . Pathogenesis and pharmacological strategies for mitigating secondary damage in acute spinal cord injury. Neurosurgery 1999; 44: 1027–1039.
Lu J, Ashwell KW, Waite P . Advances in secondary spinal cord injury: role of apoptosis. Spine 2000; 25: 1859–1866.
Geisler FH, Dorsey FC, Coleman WP . Recovery of motor function after spinal-cord injury – a randomized, placebo-controlled trial with GM-1 ganglioside. N Engl J Med 1991; 324: 1829–1838.
Haghighi SS, Johnson GC, de Vergel CF, Vergel Rivas BJ . Pretreatment with NMDA receptor antagonist MK801 improves neurophysiological outcome after an acute spinal cord injury. Neurol Res 1996; 18: 509–515.
Bracken MB et al. Efficacy of methylprednisolone in acute spinal cord injury. JAMA 1984; 251: 45–52.
Bracken MB et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 1990; 322: 1405–1411.
Bracken MB et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 1997; 277: 1597–1604.
Balentine JD . Pathology of experimental spinal cord trauma. I. The necrotic lesion as a function of vascular injury. Lab Invest 1978; 39: 236–253.
Crowe MJ, Bresnahan JC, Shuman SL, Masters JN, Beattie MS . Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med 1997; 3: 73–76.
Liu XZ et al. Neuronal and glial apoptosis after traumatic spinal cord injury. J Neurosci 1997; 17: 5395–5406.
Benowitz LI et al. Axon outgrowth is regulated by an intracellular purine-sensitive mechanism in retinal ganglion cells. J Biol Chem 1998; 273: 29626–29634.
Benowitz LI, Goldberg DE, Madsen JR, Soni D, Irwin N . Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury. Proc Natl Acad Sci USA 1999; 96: 13486–13490.
Litsky ML, Hohl CM, Lucas JH, Jurkowitz MS . Inosine and guanosine preserve neuronal and glial cell viability in mouse spinal cord cultures during chemical hypoxia. Brain Res 1999; 821: 426–432.
Hasko G et al. Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. J Immunol 2000; 164: 1013–1019.
Marton A et al. Anti-inflammatory effects of inosine in human monocytes, neutrophils and epithelial cells in vitro. Int J Mol Med 2001; 8: 617–621.
Shi M, You SW, Meng JH, Ju G . Direct protection of inosine on PC12 cells against zinc-induced injury. Neuroreport 2002; 13: 477–479.
Wu MM, You SW, Hou B, Jiao XY, Li YY, Ju G . Effects of inosine on axonal regeneration of axotomized retinal ganglion cells in adult rats. Neurosci Lett 2003; 341: 84–86.
Hou B et al. Neuroprotective effect of inosine on axotomized retinal ganglion cells in adult rats. Invest Ophthalmol Vis Sci 2004; 45: 662–667.
Hasko G, Sitkovsky MV, Szabo C . Immunomodulatory and neuroprotective effects of inosine. Trends Pharmacol Sci 2004; 25: 152–157.
Shu SY, Ju G, Fan LZ . The glucose oxidase-DAB-nickel method in peroxidase histochemistry of the nervous system. Neurosci Lett 1988; 85: 169–171.
Liu F et al. Significance of fixation of the vertebral column for spinal cord injury experiments. Spine 2003; 28: 1666–1671.
Casha S, Yu WR, Fehlings MG . Oligodendroglial apoptosis occurs along degenerating axons and is associated with FAS and p75 expression following spinal cord injury in the rat. Neuroscience 2001; 103: 203–218.
Kharlamov A, Uz T, Joo JY, Manev H . Pharmacological characterization of apoptotic cell death in a model of photothrombotic brain injury in rats. Brain Res 1996; 734: 1–9.
Isenmann S, Stoll G, Schroeter M, Krajewski S, Reed JC, Bahr M . Differential regulation of Bax, Bcl-2, and Bcl-X proteins in focal cortical ischemia in the rat. Brain Pathol 1998; 8: 49–62.
Grasl-Kraupp B, Ruttkay-Nedecky B, Koudelka H, Bukowska K, Bursch W, Schulte-Hermann R . In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology 1995; 21: 1465–1468.
Chen P, Goldberg DE, Kolb B, Lanser M, Benowitz LI . Inosine induces axonal rewiring and improves behavioral outcome after stroke. Proc Natl Acad Sci USA 2002; 99: 9031–9036.
Haun SE, Segeleon JE, Trapp VL, Clotz MA, Horrocks LA . Inosine mediates the protective effect of adenosine in rat astrocyte cultures subjected to combined glucose-oxygen deprivation. J Neurochem 1996; 67: 2051–2059.
Hooper DC et al. Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci USA 1998; 95: 675–680.
Virag L, Szabo C . Purines inhibit poly(ADP-ribose) polymerase activation and modulate oxidant-induced cell death. FASEB J 2001; 15: 99–107.
Hsu CY, Dimitrijevic MR . Methylprednisolone in spinal cord injury: the possible mechanism of action. J Neurotrauma 1990; 7: 115–119.
Acknowledgements
This work was supported by the research Grants from the National Basic Research Program of China (2003CB515031) and Natural Science Foundation of China (30371466). The authors thank Drs Bai-Ren Wang and Wei-Lin Jin for their helpful comments on the manuscript.
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Liu, F., You, SW., Yao, LP. et al. Secondary degeneration reduced by inosine after spinal cord injury in rats. Spinal Cord 44, 421–426 (2006). https://doi.org/10.1038/sj.sc.3101878
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DOI: https://doi.org/10.1038/sj.sc.3101878
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