Time course of post-traumatic mitochondrial oxidative damage and dysfunction in a mouse model of focal traumatic brain injury: implications for neuroprotective therapy

• Published in: Journal of cerebral blood flow and metabolism Vol. 26; no. 11; pp. 1407 - 1418
• Main Authors: Singh, Indrapal N, Sullivan, Patrick G, Deng, Ying, Mbye, Lamin H, Hall, Edward D
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.11.2006; Lippincott Williams & Wilkins; Sage Publications Ltd
• Subjects: Animals; Biological and medical sciences; Blotting, Northern; Brain Hemorrhage, Traumatic - drug therapy; Brain Hemorrhage, Traumatic - metabolism; Brain Hemorrhage, Traumatic - pathology; Calpain - physiology; Cytoskeleton - pathology; Injuries of the nervous system and the skull. Diseases due to physical agents; Male; Medical sciences; Membrane Lipids - metabolism; Membrane Proteins - metabolism; Mice; Microscopy, Electron; Mitochondria - metabolism; Mitochondria - pathology; Nerve Degeneration; Neurology; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - therapeutic use; Oxidative Stress - drug effects; Oxygen Consumption - physiology; Peroxynitrous Acid - metabolism; Pharmacology. Drug treatments; Reactive Oxygen Species; Traumas. Diseases due to physical agents; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Vascular diseases and vascular malformations of the nervous system; mitochondrial permeability transition; traumatic brain injury; oxidative damage; mitochondria; Nervous system diseases; Rodentia; Permeability; Cerebral disorder; Vertebrata; Mitochondria; Mammalia; Treatment; Mouse; Animal; Central nervous system disease; Transition; Head trauma; Cerebrovascular disease
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/sj.jcbfm.9600297

In the present study, we investigate the hypothesis that mitochondrial oxidative damage and dysfunction precede the onset of neuronal loss after controlled cortical impact traumatic brain injury (TBI) in mice. Accordingly, we evaluated the time course of post-traumatic mitochondrial dysfunction in the injured cortex and hippocampus at 30 mins, 1, 3, 6, 12, 24, 48, and 72 h after severe TBI. A significant decrease in the coupling of the electron transport system with oxidative phosphorylation was observed as early as 30 mins after injury, followed by a recovery to baseline at 1 h after injury. A statistically significant (P < 0.0001) decline in the respiratory control ratio was noted at 3 h, which persisted at all subsequent time-points up to 72 h after injury in both cortical and hippocampal mitochondria. Structural damage seen in purified cortical mitochondria included severely swollen mitochondria, a disruption of the cristae and rupture of outer membranes, indicative of mitochondrial permeability transition. Consistent with this finding, cortical mitochondrial calcium-buffering capacity was severely compromised by 3h after injury, and accompanied by significant increases in mitochondrial protein oxidation and lipid peroxidation. A possible causative role for reactive nitrogen species was suggested by the rapid increase in cortical mitochondrial 3-nitrotyrosine levels shown as early as 30 mins after injury. These findings indicate that post-traumatic oxidative lipid and protein damage, mediated in part by peroxynitrite, occurs in mitochondria with concomitant ultrastructural damage and impairment of mitochondrial bioenergetics. The data also indicate that compounds which specifically scavenge peroxynitrite (ONOO) or ONOO−derived radicals (e.g. ONOO− + H+ → ONOOH → †NO2 + †OH) may be particularly effective for the treatment of TBI, although the therapeutic window for this neuroprotective approach might only be 3 h.