Development of a chronic compression spinal cord injury model in neonatal and adult rats

Abstract

Background: Spinal cord injury presents a significant burden globally, with traumatic spinal cord injury being the predominant cause historically. However, nontraumatic spinal cord injury (NTSCI) is emerging as a significant contributor, particularly in developed nations, yet it remains poorly understood due to underreporting and misclassification. NTSCI, spanning various etiologies such as bony growths, vascular conditions, infections, neoplastic conditions, and immune disorders, poses unique challenges in diagnosis and treatment, often resulting in lifelong morbidity. This study addresses the lack of suitable animal models for NTSCI research, especially in neonatal animals.

Methods: Utilizing a solid spacer approach, we developed a compression NTSCI model applicable to both neonatal and adult Sprague–Dawley rats.

Results: Through anatomical measurements and in vivo experiments, we confirmed the feasibility and safety of the spacer insertion procedure and observed no acute off-target effects.

Conclusion: The versatility of this model lies in its adaptability to different ages of rats, offering a cost-effective and reproducible means to induce graded injuries. Moreover, behavioral assessments demonstrated observable hindlimb function, validating the model’s utility for studying functional outcomes. Although challenges persist, particularly in accounting for spinal column growth in neonatal animals, this model fills a crucial gap in pediatric NTSCI research. By providing a platform to investigate pathophysiological mechanisms and test potential treatments, it offers promising avenues for advancing our understanding and management of pediatric NTSCI.

Keywords

animal models / neonatal / neuroscience / reproducibility / spinal cord

References

[1] Ding W, Hu S, Wang P, et al. Spinal cord injury: the global incidence, prevalence, and disability from the Global Burden of Disease Study 2019. Spine (Phila Pa 1976). 2022;47(21):1532-1540.

[2] Barbiellini Amidei C, Salmaso L, Bellio S, Saia M. Epidemiology of traumatic spinal cord injury: a large population-based study. Spinal Cord. 2022;60(9):812-819.

[3] Buzzell A, Chamberlain JD, Eriks-Hoogland I, et al. All-cause and cause-specific mortality following non-traumatic spinal cord injury: evidence from a population-based cohort study in Switzerland. Spinal Cord. 2020;58(2):157-164.

[4] Conti A, Campagna S, Gianino MM, et al. Incidence and mortality of spinal cord injury from 2008 to 2020: a retrospective population-based cohort study in the Piedmont region, Italy. Spinal Cord. 2023;61(2):99-105.

[5] Lee B-S, Kim O, Ham D. Epidemiologic changes in nontraumatic spinal cord injury for the last 30 years (1990–2019) in South Korea. Spinal Cord. 2022;60(3):268-273.

[6] Cunha NSC, Malvea A, Sadat S, Ibrahim GM, Fehlings MG. Pediatric spinal cord injury: a review. Children (Basel). 2023;10(9):1456.

[7] Molinares DM, Gater DR, Daniel S, Pontee NL. Nontraumatic spinal cord injury: epidemiology, etiology and management. Journal of Personalized Medicine. 2022;12(11):1872.

[8] Smith É, Fitzpatrick P, Lyons F, Morris S, Synnott K. Epidemiology of non-traumatic spinal cord injury in Ireland—a prospective population-based study. J Spinal Cord Med. 2022;45(1):76-81.

[9] New PW. A narrative review of pediatric nontraumatic spinal cord dysfunction. Topics in Spinal Cord Injury Rehabilitation. 2019;25(2):112-120.

[10] Smith E, Finn S, Fitzpatrick P. Epidemiology of pediatric traumatic and acquired nontraumatic spinal cord injury in Ireland. Top Spinal Cord Inj Rehabil. 2017;23(3):279-284.

[11] New PW, Cripps RA, Bonne Lee B. Global maps of non-traumatic spinal cord injury epidemiology: towards a living data repository. Spinal Cord. 2014;52(2):97-109.

[12] New PW, Sundararajan V. Incidence of non-traumatic spinal cord injury in Victoria, Australia: a population-based study and literature review. Spinal Cord. 2008;46(6):406-411.

[13] Patel NP, Payne CA, Patel BM. Spinal cord compression. Evidence-Based Neurology: Management of Neurological Disorders. John Wiley & Sons, Ltd.; 2015:67-74.

[14] New PW, Baxter D, Noonan VK. Estimating the incidence and prevalence of traumatic spinal cord injury in Australia. Arch Phys Med Rehabil. 2015;96(1):76-83.

[15] Ridlen R, McGrath K, Gorrie CA. Animal models of compression spinal cord injury. J Neurosci Res. 2022;100:2201-2212.

[16] Batchelor P, Kerr N, Gatt A, et al. Hypothermia prior to decompression: buying time for treatment of acute spinal cord injury. J Neurotrauma. 2010;27(8):1357-1368.

[17] Dimar J, Glassman S, Raque G, Zhang YP, Shields C. The influence of spinal canal narrowing and timing of decompression on neurologic recovery after spinal cord contusion in a rat model. Spine (Phila Pa 1976). 1999;24(16):1623-1633.

[18] Kubota K, Saiwai H, Kumamaru H, et al. Neurological recovery is impaired by concurrent but not by asymptomatic pre-existing spinal cord compression after traumatic spinal cord injury. Spine (Phila Pa 1976). 2012;37(17):1448-1455.

[19] Schiaveto-de-Souza A, Da-Silva CA, Defino HLA, Bel EAD. Effect of melatonin on the functional recovery from experimental traumatic compression of the spinal cord. Braz J Med Biol Res. 2013;46(4):348-358.

[20] Gage GJ, Kipke DR, Shain W. Whole animal perfusion fixation for rodents. J Vis Exp. 2012;28(65):e3564.

[21] Schindelin J, Arganda-Carreras I, Frise E, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9(7):676-682.

[22] Sutherland TC, Mathews KJ, Mao Y, Nguyen T, Gorrie CA. Differences in the cellular response to acute spinal cord injury between developing and mature rats highlights the potential significance of the inflammatory response. Front Cell Neurosci. 2016;10:310.

[23] Sutherland TC, Ricafrente A, Gomola K, O’Brien BA, Gorrie CA. Neonatal rats exhibit a predominantly anti-inflammatory response following spinal cord injury. Dev Neurosci. 2021;43(1):18-26.

[24] Jamon M, Maloum I, Riviere G, Bruguerolle B. Air-stepping in neonatal rats: a comparison of L-Dopa injection and olfactory stimulation. Behav Neurosci. 2002;116(6):1014-1021.

[25] Yang JF, Stephens MJ, Vishram R. Infant stepping: a method to study the sensory control of human walking. J Physiol. 1998;507(3):927-937.

[26] Forssberg H, Grillner S. The locomotion of the acute spinal cat injected with clonidine i.v. Brain Res. 1973;50(1):184-186.

[27] Forssberg H, Grillner S, Halbertsma J, Rossignol S. The locomotion of the low spinal cat. II. Interlimb coordination. Acta Physiol Scand. 1980;108(3):283-295.

[28] Harnie J, Doelman A, de Vette E, et al. The recovery of standing and locomotion after spinal cord injury does not require task-specific training. elife. 2019;8:e50134.

[29] Basso DM, Beattie MS, Bresnahan JC. Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol. 1996;139(2):244-256.

[30] Metz GA, Whishaw IQ. The ladder rung walking task: a scoring system and its practical application. J Vis Exp. 2009;28:e1204.

[31] Brower M, Grace M, Kotz CM, Koya V. Comparative analysis of growth characteristics of Sprague Dawley rats obtained from different sources. Lab Anim Res. 2015;31(4):166-173.

[32] Fehlings MG, Vaccaro A, Wilson JR, et al. Early versus delayed decompression for traumatic cervical spinal cord injury: results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS). PLoS One. 2012;7(2):e32037.

[33] Jain NB, Ayers GD, Peterson EN, et al. Traumatic spinal cord injury in the United States, 1993–2012. JAMA. 2015;313(22):2236-2243.

RIGHTS & PERMISSIONS

2024 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.