Assessment of rat spinal cord injury models

Traumatic spinal cord injury (SCI) is a complicated and devastating condition, causing different extents of motor, sensory and autonomic dysfunctions. In addition, there is a risk for secondary complications after SCI including posttraumatic syringomyelia (PTS) that can cause further functional loss. Since there is no available effective treatment, tremendous efforts have been made to develop new therapeutic strategies to promote functional recovery after SCI. In experimental research, it is important to utilize model systems, including in vivo models that mimic the clinical situation to develop new treatments. Furthermore, multiple tests should be applied to comprehensively evaluate the models and novel treatments.

We developed two assessment tools for swimming and wading in rats with SCI, with the sensitivity to injury severities from the most severe to the very mildest. Both the Karolinska Institutet Swim Assessment Tool (KSAT) and the wading scale consist of six parameters, reflecting different functional aspects. KSAT and Wading scores for four experimental groups of different injury severity consistently displayed the functional improvement after injury. The internal consistency, inter-rater and test-retest reliability were all very high. We also found a high correlation between KSAT/Wading score and spared white matter at injury epicenter, and between the KSAT, wading and BBB scores.

In addition, we studied kinematic analysis of swimming in two SCI models (mild contusion and compression SCIs) and a control group by a simple two-dimensional system representing the hindlimbs with 3 segments and 2 angles, analyzing six parameters. The results showed that three parameters Swim Speed, Stroke Time and Extension time/Flexion time changed significantly between week 2 and 8. The results of Swim Speed, Angular Velocity and Stroke Time at week 8 were highly correlated with spared tissue at injury epicenter, particularly in contusion SCI. However, for these parameters there was overlap between very mildly injured rats and controls, not achieving the same sensitivity as the KSAT score.

To study neural cell therapy of PTS, we developed a novel rat model mimicking the clinical situation. We used a combination of mild low thoracic contusion trauma and subarachnoid injection of autologous venous blood. The injured rats developed cysts that were extracanalicular, mainly rostral to the injury and lined with astrocytes. T2-weighted magnetic resonance imaging (MRI) scanned 20 weeks after injury showed hyperintense fluid-filled cysts and hypointense areas of tissue degeneration with iron-laden macrophages/microglia. However, the functional analysis did not reveal deterioration coinciding with cyst expansion. Under the guidance of MRI, human neural precursor cells (hNPCs) were transplanted into the cysts. The hNPCs survived, covered the surface of the cyst walls and migrated into surrounding tissue. Moreover, the cells partially obliterated the cysts and in some areas merged the walls of the cysts.

In conclusion, KSAT and wading scale were found to be reliable tools to assess motor activity in swimming and wading, while kinematic analysis did not prove to be very useful for functional testing. The new rat PTS model closely mimics the pathophysiological and anatomical features of the clinical situation. Using this model, transplantation of hNPCs was shown to be a potential treatment to obliterate cysts in PTS.

List of scientific papers

I. Ning Xu, Elisabet Åkesson, Lena Holmberg, Erik Sundström. A sensitive and reliable test instrument to assess swimming in rats with spinal cord injury. Behav Brain Res., 2015, 15(291): 172-83.
https://doi.org/10.1016/j.bbr.2015.05.004

II. Ning Xu, Sreenivasa Sankavaram, Lou Brundin, Elisabet Åkesson, Lena Holmberg, Erik Sundström. Detailed analysis of motor performance during swimming and wading in rats with spinal cord injury. [Manuscript]

III. Ning Xu, Raymond Mirasol, Lena Holmberg, Per Henrik Vincent, Eva-Britt Samuelsson, Erikur Benedikz, Bartosz Bezubik, Emilia Rothstein, Lars-Olof Wahlund, Åke Seiger, Elisabet Åkesson, Scott Falci, Erik Sundström. Transplantation of human neural precursor cells to a rat model of posttraumatic syringomyelia.[Submitted]