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Project

Mitochondrial-targeted neuroprotection following spinal cord injury.

Funder: Craig H Neilsen Foundation

Funding period
USD 275 K
Funding amount
Abstract
Approximately 255,702 Americans are living with the typically devastating neurological limitations that are secondary to SCI (http://www.spinalcord.uab.edu). With the exception of the modestly effective methylprednisolone and/or tirilazad, there is presently no clinical pharmacological intervention indicated for SCI that can be administered in the acute stages of trauma to prevent the secondary injury that ultimately limits any potential recovery from paralysis. We have documented that oxidative damage to key mitochondrial enzymes and subsequent mitochondrial dysfunction is pivotal to the neuropathological sequela following SCI. This proposal focuses on targeting mitochondrial dysfunction directly as a novel therapeutic intervention for contusion SCI; the fundamental concept being that SCI-induced excitotoxicity increases mitochondrial Ca2+ cycling/overload and the production of reactive oxygen species (ROS), ultimately leading to mitochondrial dysfunction and glutathione (GSH) depletion. Our approach is two-pronged, aimed at reducing mitochondrial ROS production utilizing a novel, cell-permeant antioxidant and GSH precursor, NACA (the amide form of N-acetylcysteine), as well as an alternative biofuel substrate for energy production, acetyl-l-carnitine (ALC), following SCI. Our published and preliminary data signify that both NACA and ALC improve mitochondrial bioenergetics and increase tissue sparing following SCI. In this project, we will test the novel hypothesis that reducing oxidative damage to key mitochondrial proteins maintains mitochondrial bioenergetics, thus leading to increased neuroprotection and improved functional recovery following contusion SCI. Therefore, we propose to treat injured patients at the scenes of trauma with a novel antioxidant approach to prevent the spread of damaged spinal cord tissues. Targeting mitochondrial dysfunction and fostering acute neuroprotection may render the greatest functional recovery and independence of affected individuals. (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

    Neurosciences

  • RCDC

    Complementary and Alternative Medicine

  • RCDC

    Spinal Cord Injury

  • RCDC

    Neurodegenerative

  • HRCS HC

    Neurological

  • HRCS RAC

    5.1 Pharmaceuticals

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science