Get access

Differential effects of the mitochondrial uncoupling agent, 2,4-dinitrophenol, or the nitroxide antioxidant, Tempol, on synaptic or nonsynaptic mitochondria after spinal cord injury

Authors

  • Samir P. Patel,

    1. Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky
    2. Department of Physiology, University of Kentucky, Lexington, Kentucky
    Search for more papers by this author
    • The first two authors contributed equally to this study.

  • Patrick G. Sullivan,

    1. Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky
    2. Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky
    Search for more papers by this author
    • The first two authors contributed equally to this study.

  • Jignesh D. Pandya,

    1. Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky
    2. Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky
    Search for more papers by this author
  • Alexander G. Rabchevsky

    Corresponding author
    1. Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky
    2. Department of Physiology, University of Kentucky, Lexington, Kentucky
    • Spinal Cord & Brain Injury Research Center (SCoBIRC), B471, Biomedical & Biological Sciences Research Building, 741 South Limestone Street, Lexington, KY 40536-0509
    Search for more papers by this author

Abstract

We recently documented the progressive nature of mitochondrial dysfunction over 24 hr after contusion spinal cord injury (SCI), but the underlying mechanism has not been elucidated. We investigated the effects of targeting two distinct possible mechanisms of mitochondrial dysfunction by using the mitochondrial uncoupler 2,4-dinitrophenol (2,4-DNP) or the nitroxide antioxidant Tempol after contusion SCI in rats. A novel aspect of this study was that all assessments were made in both synaptosomal (neuronal)- and nonsynaptosomal (glial and neuronal soma)-derived mitochondria 24 hr after injury. Mitochondrial uncouplers target Ca2+ cycling and subsequent reactive oxygen species production in mitochondria after injury. When 2,4-DNP was injected 15 and 30 min after injury, mitochondrial function was preserved in both populations compared with vehicle-treated rats, whereas 1 hr postinjury treatment was ineffective. Conversely, targeting peroxynitrite with Tempol failed to maintain normal bioenergetics in synaptic mitochondria, but was effective in nonsynaptic mitochondria when administered 15 min after injury. When administered at 15 and 30 min after injury, increased hydroxynonenal, 3-NT, and protein carbonyl levels were significantly reduced by 2,4-DNP, whereas Tempol only reduced 3-NT and protein carbonyls after SCI. Despite such antioxidant effects, only 2,4-DNP was effective in preventing mitochondrial dysfunction, indicating that mitochondrial Ca2+ overload may be the key mechanism involved in acute mitochondrial damage after SCI. Collectively, our observations demonstrate the significant role that mitochondrial dysfunction plays in SCI neuropathology. Moreover, they indicate that combinatorial therapeutic approaches targeting different populations of mitochondria holds great potential in fostering neuroprotection after acute SCI. © 2008 Wiley-Liss, Inc.

Get access to the full text of this article

Ancillary