Repairing the Injured Spinal Cord using Pleiotrophin and Rehabilitative Training

• Author / Creator

  Ng, Carmen

• Background: Functional recovery following a spinal cord injury (SCI) is linked to neuroplasticity, including neurite outgrowth and rewiring of neuronal connections rostral and caudal to the injury. Plasticity promoting treatments can be targeted to specific locations within the central nervous system (CNS) to encourage functional recovery and minimize side effects such as pain or spasticity caused by aberrant or unwanted connections. However, the optimal location(s) to promote beneficial plasticity have not yet been identified which poses a significant translational challenge.
  My research explores the use of pleiotrophin (PTN) as a neuroplasticity promoting treatment. PTN is an endogenously occurring growth factor with a unique dual nature that neutralizes growth inhibitory chondroitin sulfate proteoglycan (CSPGs) and upregulates growth promoting pathways within neurons. To develop PTN as a plasticity promoting treatment, my thesis aimed to identify a dose of PTN that would maximize neurite outgrowth from the corticospinal tract (CST), to determine which location(s) of PTN administration (e.g., rostral or caudal of an SCI) would encourage the most functional recovery, and to assess whether PTN treatment combined with rehabilitative training would elicit a complementary effect on functional recovery.

  Methodology: PTN was applied onto cortical cell cultures grown on CSPGs at concentrations of 1.25 µg/mL or 10 µg/mL to ensure our supply of PTN could promote neurite outgrowth at a level similar to published studies. The efficacy of our PTN was also screened using in vivo rat models of SCI and compared to chondroitinase ABC (ChABC), an alternative plasticity promoting treatment that acts only by digesting CSPGs. PTN and ChABC was administered into the intermediate grey matter of the spinal cord to target CSPGs within the perineuronal network (PNN) that act to stabilize neuronal connections. To identify the optimal dose of PTN, an in vivo dose-response experiment was conducted using a C4 dorsolateral quadrant (DLQ) rat model of SCI. Neurite outgrowth from the CST was compared between rats receiving different concentrations of PTN treatment and between male and female rats for any potential sex differences. We then used a contusion model of SCI to assess the effects of PTN treatment targeted to different locations in the spinal cord. PTN treatment was targeted bilaterally rostral and caudal to the SCI into the intermediate grey matter of the spinal cord. Targeted PTN treatment was combined with rehabilitative training using the single pellet grasping (SPG) task as a measure of functional recovery. Following the contusion model, a DLQ model of SCI was used to assess the effects of PTN treatment targeted into the intermediate grey matter ipsilesional and caudal to the SCI. PTN treatment was also combined with SPG training to assess functional recovery in PTN treated rats compared to PBS treated SCI rats.

  Principal Findings: Our results indicate that different concentrations of PTN elicit different extents of neurite outgrowth and PTN induced neurite outgrowth may differ between sexes. PTN treatment targeted to different locations in the spinal cord did not alter the quantity of midline crossing fibers rostral or caudal to the SCI compared to PBS treated rats. Paradoxically, PTN treated rats performed worse than PBS treated rats in the SPG task in both the contusion and DLQ models of SCI. There may be several factors contributing to the difference in SPG performance between PTN and PBS treated rats. Firstly, it could be that PTN treatment induces tissue damage that was not detected from our methods of histological analysis. Secondly, differences in SPG performance may be due to alterations in the neuronal circuitry controlling sensory signalling in PTN treated rats. Lastly, PTN treated rats had less synaptic density in the ventral horn of the spinal cord potentially indicating a decrease in neuronal connections controlling motor function.

  Conclusions: PTN can influence neuroplasticity and functional outcomes following a SCI. However, further investigation is needed to elucidate the exact anatomical changes underlying the worse functional outcomes in PTN treated rats.

• Subjects / Keywords

  • Spinal Cord Injury
  • Pleiotrophin
  • Rehabilitative Training
  • Neuroplasticity
  • Single Pellet Grasping Task

• Graduation date

  Spring 2023

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-dvhr-dd89

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.