Spinal Cord Contusion in Rats Treated with Systemic Hypothermia. Experimental Cold-inducible Protein Expression
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Published:
Jun 17, 2024
Keywords:
Contusion, hypothermia, spinal cord, CIRBP, rat, injury
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Abstract
Introduction: Traumatic spinal cord injury is the leading cause of motor disability worldwide, and the WHO considers it a priority. This study sought to investigate the effects of therapeutic hypothermia following spinal cord contusion.
Materials and Methods: Male rats that underwent experimental spinal cord contusion were used. For this purpose, four experimental groups were created (n=6 per group): a) control, b) lesion in normothermia (24°C, sacrificed 12h after the injury), c) lesion in normothermia (24°C, sacrificed 24h after the injury), and d) hypothermic injury (8°C for 180 min, sacrificed 24h after the injury). The expression of coldinducible RNA-binding protein (CIRBP), Caspase-3, and NeuN was studied.
Results: At 24 hours, spinal cord damage raised CIRBP expression slightly while also increasing Caspase-3 significantly. All of this was accompanied by images of damaged motor neurons in the anterior horn. In animals treated with hypothermia, high expression of CIRBP and very low levels of Caspase-3 were observed, which were indistinguishable from controls. Furthermore, the number of viable motor neurons was partially restored.
Conclusions: The experimental model developed in this study was effective at inducing spinal cord injury, demonstrating neuronal protection through hypothermia. The increased expression of CIRBP in the spinal cord of rats with injury and hypothermic treatment when compared to the normothermic group suggests the possibility of using substances that increase CIRBP as therapies for the treatment of contusive spinal cord injuries.
Materials and Methods: Male rats that underwent experimental spinal cord contusion were used. For this purpose, four experimental groups were created (n=6 per group): a) control, b) lesion in normothermia (24°C, sacrificed 12h after the injury), c) lesion in normothermia (24°C, sacrificed 24h after the injury), and d) hypothermic injury (8°C for 180 min, sacrificed 24h after the injury). The expression of coldinducible RNA-binding protein (CIRBP), Caspase-3, and NeuN was studied.
Results: At 24 hours, spinal cord damage raised CIRBP expression slightly while also increasing Caspase-3 significantly. All of this was accompanied by images of damaged motor neurons in the anterior horn. In animals treated with hypothermia, high expression of CIRBP and very low levels of Caspase-3 were observed, which were indistinguishable from controls. Furthermore, the number of viable motor neurons was partially restored.
Conclusions: The experimental model developed in this study was effective at inducing spinal cord injury, demonstrating neuronal protection through hypothermia. The increased expression of CIRBP in the spinal cord of rats with injury and hypothermic treatment when compared to the normothermic group suggests the possibility of using substances that increase CIRBP as therapies for the treatment of contusive spinal cord injuries.
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Sarotto, A. J., Toscanini, M. A., Contartese, D., Dorfman, V. B., Nakamura, R., Besse, M., Larráyoz, I. M., Martínez , A., De Matteo, E., Rey-Funes, M., & Loidl, C. F. (2024). Spinal Cord Contusion in Rats Treated with Systemic Hypothermia. Experimental Cold-inducible Protein Expression. Revista De La Asociación Argentina De Ortopedia Y Traumatología, 89(3), 299-313. https://doi.org/10.15417/issn.1852-7434.2024.89.3.1866
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24. Larrayoz IM, Rey-Funes M, Contartese DS, Rolón F, Sarotto A, Dorfman VB, et al. Cold shock proteins are
expressed in the retina following exposure to low temperatures. PLoS One 2016;24;11(8):e0161458.
https://doi.org/10.1371/journal.pone.0161458
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2. Ministerio de Salud de la Nación Argentina. Anuario estadístico nacional sobre discapacidad del año 2013.
Disponible en: https://www.snr.gov.ar/publicacion
3. Dorfman VB, Rey-Funes M, Bayona JC, López EM, Coirini H, Loidl CF. Nitric oxide system alteration at spinal
cord as a result of perinatal asphyxia is involved in behavioral disabilities: hypothermia as preventive treatment. J
Neurosci Res 2009;87(5):1260-9. https://doi.org/10.1002/jnr.21922
4. Loidl CF. Short and long term effects of perinatal asphyxia. Thesis. Netherlands: Maastricht University; 1997.
5. Loidl CF, De Vente J, van Dijk E, Vles SH, Steinbusch H, Blanco C. Hypothermia during or after severe
perinatal asphyxia prevents increase in cyclic GMP-related nitric oxide levels in the newborn rat striatum. Brain
Res 1998;791(1-2):303-7. https://doi.org/10.1016/s0006-8993(98)00195-4
6. Peña M, Rey-Funes M, Sarotto A, Loidl FC. Estudio del patrón migratorio de neuronas corticofrontales que
expresan reelina en la asfixia perinatal experimental. Medicina (Buenos Aires) 2012;72(Supl II) Neurociencias 4 369p. 157. Disponible en: https://medicinabuenosaires.com/demo/revistas/vol72-12/supl-2/53-252-SAIC-Resumenes72-2012.pdf
7. Rey-Funes M, Ibarra ME, Dorfman VB, López EM, López-Costa JJ, Coirini H, et al. Hypothermia prevents
the development of ischemic proliferative retinopathy induced by severe perinatal asphyxia. Exp Eye Res
2010;90(1):113-20. https://doi.org/10.1016/j.exer.2009.09.019
8. Rey-Funes M, Ibarra M, Dorfman VB, Martinez-Murillo R, Martinez A, Coirini H, et al. Hypothermia prevents
nitric oxide system changes in retina induced by severe perinatal asphyxia. J Neurosci Res 2011;89(5):729-43.
https://doi.org/10.1002/jnr.22556
9. Rey-Funes M, Dorfman VB, Ibarra M, Peña E, Contartese DS, Goldstein J, et al. Hypothermia prevents gliosis and angiogenesis development in an experimental model of ischemic proliferative retinopathy. Invest Ophthalmol Vis Sci 2013;54(4):2836-46. https://doi.org/10.1167/iovs.12-11198
10. Rey-Funes M, Contartese DS, Rolón F, Sarotto A, Dorfman VB, Loidl CF. Efecto protector de la hipotermia
en la retinopatía del prematuro (ROP) experimental. Rol de las proteínas inducibles por frío. Arch Argent
Oftalm 2016;(6):45-56. Disponible en: https://archivosoftalmologia.com.ar/index.php/revista/issue/view/17/13
11. Rey-Funes M, Larrayoz IM, Contartese DS, Soliño M, Sarotto AJ, Bustelo M, et al. Hypotermia prevents retinal
damage generated by optic nerve trauma in the rat. Sci Rep 2017;7(1):6966. https://doi.org/10.1038/s41598-017-07294-6
12. Sarotto AJ, Rey-Funes M, Dorfman VB, Contartese D, Larráyoz IM, Martínez A, et al. Expresión de proteínas
inducibles por frío en la médula espinal de rata sometida a hipotermia sistémica. Rev Asoc Argent Ortop
Traumatol 2022;87(3):393-403. https://doi.org/10.15417/issn.1852-7434.2022.87.3.1488
13. Contartese DS, Rey-Funes M, Sarotto A, Dorfman VB, Loidl CF, Martínez A. A hypothermia mimetic molecule
(zr17-2) reduces ganglion cell death and electroretinogram distortion in a rat model of intraorbital optic nerve crush (IONC). Front Pharmacol 2023;14:1112318. https://doi.org/10.3389/fphar.2023.1112318
14. Lo TP, Cho K-S, Garg MS, Lynch MP, Marcillo AE, Koivisto DL, et al. Systemic hypothermia improves histological
and functional outcome after cervical spinal cord contusion in rats. J Comp Neurol 2009;514(5):433-48.
https://doi.org/10.1002/cne.22014
15. Shibuya S, Miyamoto O, Janjua NA, Itano T, Mori S, Horimatsu H. Post-traumatic moderate systemic hypothermia reduces TUNEL positive cells following spinal cord injury in rat. Spinal Cord 2004;42(1):29-34.
https://doi.org/10.1038/sj.sc.3101516
16. Yu CG, Jimenez O, Marcillo AE, Weider B, Bangerter K, Dietrich WD, et al. Beneficial effects of modest systemic
hypothermia on locomotor function and histopathological damage following contusion induced spinal cord injury in rats. J Neurosurg 2000;93(1 Suppl):85-93. https://doi.org/10.3171/spi.2000.93.1.0085
17. Yu WR, Westergren H, Farooque M, Holtz A, Olsson Y. Systemic hypothermia following compression injury
of the rat spinal cord: reduction of plasma protein extravasation demonstrated by immunohistochemistry. Acta
Neuropathol 1999;98(1):15-21. https://doi.org/10.1007/s004010051046
18. Batchelor PE, Skeers P, Antonic A, Wills TE, Howells DW, Macleod MR, et al. Systematic review and metaanalysis of therapeutic hypothermia in animal models of spinal cord injury. PLoS One 2013;8(8):e71317.
https://doi.org/10.1371/journal.pone.0071317.
19. Sonna LA, Fujita J, Gaffin SL, Lilly CM. Invited review: Effects of heat and cold stress on mammalian gene
expression. J Appl Physiol (1985) 2002;92(4):17251742. https://doi.org/10.1152/japplphysiol.01143.2001
20. Al-Fageeh MB, Smales CM. Control and regulation of the cellular responses to cold shock: the responses in yeast and mammalian systems. Biochem J 2006;397(2):247-59. https://doi.org/10.1042/BJ20060166
21. Nishiyama H, Itoh K, Kaneko Y, Kishishita M, Yoshida O, Fujita J. A glycine-rich RNA-binding protein mediating
cold-inducible suppression of mammalian cell growth. J Cell Biol 1997;137(4):899-908. https://doi.org/10.1083/jcb.137.4.899
22. Tong G, Endersfelder S, Rosenthal LM, Wollersheim S, Sauer IM, Bührer C, et al. Effects of moderate and deep
hypothermia on RNA-binding proteins RBM3 and CIRP expressions in murine hippocampal brain slices. Brain
Res 2013;1504:74-84. https://doi.org/10.1016/j.brainres.2013.01.041
23. Rey-Funes M, Contartese DS, Peláez R, García-Sanmartín J, Narro-Íñiguez J, Soliño M, et al. Hypothermic shock
applied after perinatal asphyxia prevents retinal damage in rats. Front Pharmacol 2021;12:651599.
https://doi.org/10.3389/fphar.2021.651599
24. Larrayoz IM, Rey-Funes M, Contartese DS, Rolón F, Sarotto A, Dorfman VB, et al. Cold shock proteins are
expressed in the retina following exposure to low temperatures. PLoS One 2016;24;11(8):e0161458.
https://doi.org/10.1371/journal.pone.0161458
25. Young W. Spinal cord contusion models. Prog Brain Res 2002;137:231-55. https://doi.org/10.1016/s0079-6123(02)37019-5
26. Rodrigo J, Peinado MA, Pedrosa A. Avances en inmunocitoquímica y técnicas relacionadas. Jaén: Publicaciones de la Universidad de Jaén; 1996.
27. Rodrigo J, Alonso D, Fernández AP, Serrano J, Richart A, López JC, et al. Neuronal and inducible nitric oxide synthase expresión and protein nitration in rat cerebellum after oxygen and glucose deprivation. Brain Res 2001;909(1-2):20-45. https://doi.org/10.1016/s0006-8993(01)02613-0
28. Wrathall JR. Spinal cord injury models. J Neurotrauma 1992;9(Suppl 1):S129-34. PMID: 1588603
29. Fehlings MG, Tator CH. A review of experimental models of acute spinal cord injury. En: Illis LS (ed.). Spinal
cord dysfunction: assessment. Oxford: Oxford University; 1988, p. 3-43.
30. Parent S, Mac-Thiong JM, Roy-Beaudry M, Sosa JF, Labelle H. Spinal cord injury in the pediatric population: a
systematic review of the literature. J Neurotrauma 2011;28(8):1515-24. https://doi.org/10.1089/neu.2009.1153
31. Kundi S, Bicknell R, Ahmed Z. Spinal cord injury: current mammalian models. Am J Neurosci 2013;4(1):1-12.
https://doi.org/10.3844/ajnsp.2013.1.12
32. Cambria RP, Davison JK. Regional hypothermia for prevention of spinal cord ischemic complications after
thoracoabdominal aortic surgery: experience with epidural cooling. Semin Thorac Cardiovasc Surg 1998;10(1):61-
5. https://doi.org/10.1016/s1043-0679(98)70020-6
33. Bicknell CD, Riga CV, Wolfe JH. Prevention of paraplegia during thoracoabdominal aortic aneurysm repair. Eur J Vasc Endovasc Surg 2009;37(6):654-60. https://doi.org/10.1016/j.ejvs.2009.02.008
34. Dietrich WD III. Therapeutic hypothermia for spinal cord injury. Crit Care Med 2009;37(7 Suppl):S238-S242.
https://doi.org/10.1097/CCM.0b013e3181aa5d85
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