Differential effects of the mitochondrial uncoupling agent, 2,4‐dinitrophenol, or the nitroxide antioxidant, Tempol, on synaptic or nonsynaptic mitochondria after spinal cord injury
- 15 August 2008
- journal article
- research article
- Published by Wiley in Journal of Neuroscience Research
- Vol. 87 (1), 130-140
- https://doi.org/10.1002/jnr.21814
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.Keywords
This publication has 38 references indexed in Scilit:
- High Cyclophilin D Content of Synaptic Mitochondria Results in Increased Vulnerability to Permeability TransitionJournal of Neuroscience, 2007
- Temporal Characterization of Mitochondrial Bioenergetics after Spinal Cord InjuryJournal of Neurotrauma, 2007
- Pretreatment with the Cyclosporin Derivative, NIM811, Improves the Function of Synaptic Mitochondria following Spinal Cord Contusion in RatsJournal of Neurotrauma, 2007
- Cyclosporin a Increases Mitochondrial Calcium Uptake Capacity in Cortical Astrocytes but not Cerebellar Granule NeuronsJournal of Bioenergetics and Biomembranes, 2006
- Mitochondrial permeability transition in CNS trauma: Cause or effect of neuronal cell death?Journal of Neuroscience Research, 2004
- Tempol, a Nitroxide Antioxidant, Improves Locomotor and Histological Outcomes after Spinal Cord Contusion in RatsJournal of Neurotrauma, 2004
- The Mitochondrial Uncoupling Agent 2,4-Dinitrophenol Improves Mitochondrial Function, Attenuates Oxidative Damage, and Increases White Matter Sparing in the Contused Spinal CordJournal of Neurotrauma, 2004
- Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injuryJournal of Neurochemistry, 2004
- Mitochondrial damage and dysfunction in traumatic brain injuryMitochondrion, 2004
- Pathophysiology of spinal cord traumaAnnals of Emergency Medicine, 1993