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Project

Nimodipine promotes motor recovery after spinal cord injury

Funder: Craig H Neilsen Foundation

Funding period
USD 300 K
Funding amount
Abstract
Spinal cord injury (SCI) results in devastating impairment below the injury site, leading to paralysis, sensory dysfunction, neuropathic pain, and spasticity, dramatically reducing the patients’ quality of life. Independently of therapeutic strategy, locomotor recovery after SCI is based on a functional lumbar spinal cord. The lumbar neural circuitry undergoes maladaptive forms of plasticity leading to spasticity that develops over time after SCI. The main goal of this proposal is to examine if nimodipine, an FDA approved drug, via blockage of L-type calcium channels (Cav 1.3), prevents aberrant alteration in lumbar neural network and improves motor outcomes after cervical (SCI). Our data using constitutive knockout and deletion of CaV 1.3 shows that the Cav 1.3 channels are critical for the development and maintenance of spasticity following chronic sacral SCI. In addition to the reappearance of plateau potentials and spasticity, we have strong evidence of significant loss of lumbar motoneurons, interneurons and morphological integrity in the chronic phase of cSCI. This phenomenon has been verified in both traumatic rat cSCI and non-traumatic cSCI in reporter mice. In our first aim, we will determine the role of neuronal CaV 1.3 channels in the development of hindlimb spasticity and lumbar cord degeneration after cSCI using transgenic mouse lines currently available in the Kiehn lab. We also have evidence that nimodipine prevents the development of tail spasticity following sacral SCI in the mouse. In our second aim, we will evaluate the therapeutic and translational potential of this discovery, by assessing whether nimodipine is capable of preventing hindlimb spasticity, preserving lumbar cord neurons and facilitate motor recovery after cSCI in rats. The mechanistic experiments proposed here will address significant gaps in our knowledge about spasticity and neurodegeneration after SCI. This proposal is highly translational as nimodipine is an FDA approved drug. (CHN: SCIRTS chn:wdg)
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System

Categories
  • FOR (ANZSRC)

    1109 Neurosciences

  • RCDC

    Injury (total) Accidents/Adverse Effects

  • RCDC

    Injury - Trauma - (Head and Spine)

  • RCDC

    Regenerative Medicine

  • RCDC

    Neurosciences

  • RCDC

    Pain Research

  • RCDC

    Rehabilitation

  • RCDC

    Spinal Cord Injury

  • RCDC

    Neurodegenerative

  • HRCS HC

    Neurological

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science