A novel experimental model of cervical spondylotic myelopathy (CSM) to facilitate translational research
Introduction
Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord dysfunction among adults over the age of 55 (Young, 2000) and the key underlying risk factor predisposing patients to traumatic central cord syndrome, the most common cause of cervical spinal cord injury (SCI) (van Middendorp et al., 2010). Indeed, 25% of spinal cord dysfunction in the U.K. is caused by CSM (Moore and Blumhardt, 1997). Critical gaps in our knowledge of the pathobiology of CSM have limited therapeutic advances for this common cause of neurological dysfunction. While surgical intervention can attenuate the progression of CSM, most patients are still left with significant neurological impairment (Fehlings et al., 2012). Remarkably little translational research has been directed at developing pharmacological and biological approaches to improve outcomes for this condition. The lack of reliable rodent models of CSM has been a clear limitation to advancing the field.
To date, various attempts have been made to reproduce CSM in animal models (Karadimas et al., 2010, Klironomos et al., 2011, Lee et al., 2012). Although some of these studies have significant merit, they also have critical limitations. Most of these studies are acute or subacute in design and consequently fail to model the chronic and progressive nature of the disease. Moreover, many of these models do not accurately reproduce the main human neuropathological and clinical features of CSM, are not MRI compatible and, do not facilitate surgical decompression. These limitations and the lack of neuroprotective treatments for CSM point toward the need for a novel model. This model should result in slow, progressive compression, should produce neurological deficits that mimic the human condition, should ideally involve the mid-cervical cord segments and should allow for surgical decompression.
In this study we report, for the first time, a unique, clinically relevant model of CSM in rats. It is less invasive than previous models, reproduces the clinical symptoms and the neuropathological features of the human disease, and unlike previous models, is MRI compatible and allows for surgical decompression.
Section snippets
Compression material
A synthetic aromatic polyether was used as the compression material. Its most characteristic property is the capacity to absorb phosphate anions, increase calcium phosphate sedimentation and induce new osteoid formation (Klironomos et al., 2011).
Experimental groups & surgical procedures
A summary of the experimental groups is depicted in Table 1. All animal protocols were approved by the animal ethics committee of the University Health Network, Toronto, Ontario, Canada.
Chronic compression resulted in a significant loss of gray matter and increased scar tissue area
Rats with compressive lesions displayed cystic cavitation, scar tissue, central gray and white matter degeneration, atrophy of the anterior horn of gray matter and anterior horn cell loss on hematoxylin–eosin (HE) and Luxol Fast Blue (LFB) sections. Moreover, significant loss of gray matter area and increased scar tissue and cavity area (two-way ANOVA, p < 0.001 for each) was observed over a rostro-caudal distance of 4 mm centered on the compression epicenter (CE) and was found in the CSM (n = 6)
Discussion
In this study we characterized a novel rat model of chronic progressive cervical spinal cord compression that reflects the spatial and the temporal profiles of human disease. MRI confirmed the progressive compression as well as the feasibility of surgical decompression. This chronic progressive cord compression resulted in significant gait pattern and forelimb dysfunction similar to human CSM. Furthermore this model has facilitated the examination of microvasculature disruption, neural
Conclusion
In conclusion the novel rat CSM model, described in the current paper, produces neurological deficits and neuropathological features accurately mimicking the human condition, is MRI compatible and, importantly, allows for surgical decompression. Hence it has the potential to identify the molecular mechanisms which lead to the progression of this unique disease as well as to facilitate the discovery of novel clinically-relevant therapeutic targets for translation to human patients.
The following
Acknowledgment
The authors would like to acknowledge Warren Foltz at the STTARR facility for assistance with MR imaging and Behzad Azad for assistance with the animal care. Moreover the authors would like to acknowledge James W. Austin for sharing his research experience. This work was supported by the CIHR and the Gerald and Tootsie Halbert Chair in Neural Repair and Regeneration (MGF). We are also grateful for the financial support from the North America Spine Society (NASS). SKK was supported by a Synthes
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