Augmenting Plasticity and Recovery from Stroke by Modulating the Extracellular Matrix of the Central Nervous System

  • Author / Creator
    Wiersma, Anna M
  • Recovery following stroke occurs almost entirely in the first weeks post injury. Moreover, the efficacy of rehabilitative training is limited beyond this narrow time frame. Sprouting of spared corticospinal tract axons in the spinal cord makes a significant contribution to sensorimotor recovery, but this structural plasticity is also limited to the first few weeks after stroke. Here, we first tested the hypothesis that inducing plasticity in the spinal cord during chronic stroke could stimulate a second wave of recovery from sensorimotor impairment. We potentiated spinal plasticity during chronic stroke, weeks after the initial ischemic injury, in rats via intraspinal injections of chondroitinase ABC, an enzyme which digests inhibitory extracellular matrix proteins (chondroitin sulfate proteoglycans). Our data show that chondroitinase injections into the grey matter of the cervical spinal cord administered 28 days after stroke induced drastic sprouting of corticospinal axons and reduced sensorimotor impairments. Importantly, this therapy dramatically potentiated the efficacy of rehabilitative training delivered during chronic stroke in a skilled forelimb reaching task. To elucidate the mechanism by which chondroitinase ABC induced anatomical changes in vivo, we then investigated the direct regulation of neurite outgrowth by chondroitinase ABC cleavage byproducts in neurite cell cultures and assayed the release of the well-established anti-inflammatory molecules from isolated microglia and mixed glial cell cultures. Our data clearly demonstrates that one of the chondroitinase ABC generated cleavage stubs (C-4-S) directly promotes the outgrowth of neurites in a chondroitin sulfate proteoglycan dependent manner. We also demonstrate that the C-4-S cleavage stub induces the release of trophic and anti-inflammatory cytokines from microglia and mixed glia while attenuating the release of pro-inflammatory cytokines after biological activation of both isolated microglia and mixed glial cultures. Next, we examined the effects of exogenous administration of pleiotrophin, an endogenous growth promoting factor which binds growth inhibitory components of the extracellular matrix (chondroitin sulfate side chains), on neurite growth glial activation and glial release of immunomodulators in vitro. Our data suggests that pleiotrophin interacts with neurites in a chondroitin sulfate dependent manner to enhance outgrowth. In addition, we provide strong evidence that pleiotrophin modifies the cytokine expression profiles of microglia to favor the release of tropic factors and heightens the release of anti-inflammatory molecules following biological activation. Further, we found that pleiotrophin induced an anti-inflammatory cytokine release profile in mixed glial cell cultures when secondary inflammation was stimulated. Since recovery following stroke is limited to the first few weeks after injury, enhancing plasticity during this time may reduce chronic deficits. To evaluate the efficacy of pleiotrophin as a therapeutic for stroke, we next tested the hypothesis that enhancing plasticity in the spinal cord in the subacute period following stroke via pleiotrophin injections could stimulate enhanced recovery of sensorimotor function. Our data show that pleiotrophin injections into the grey matter of the cervical spinal cord administered 7 days after stroke reduced sensorimotor impairments without inducing chronic pain. Anatomical studies revealed heightened expression of factors associated with plasticity in the stroke deinnervated cervical spinal cord of pleiotrophin treated rats. Further, our data suggests that pleiotrophin offers a protective effect to cervical spinal motor neurons left deinnervated by stroke and induces restoration of serotonergic fibers density in the cervical spinal grey matter. Combined, the data herein offers hope of improved quality of life via reduced sensorimotor impairment for the millions who live with long term disability as a direct result of stroke.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • 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.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Centre for Neuroscience
  • Supervisor / co-supervisor and their department(s)
    • Ian Winship (Neuroscience and Psychiatry)
    • Kathryn Todd (Neuroscience)
  • Examining committee members and their departments
    • Karim Fouad (Neuroscience and Rehabilitation Medicine)
    • Patrick Whelan (Faculty of Veterinary Medicine, Faculty of Medicine and Faculty of Kinesiology)
    • Christine Webber (Neuroscience and Anatomy)