title: Pharmacological evidence for a role of peroxynitrite in the pathophysiology of spinal cord injury.
abstract: Evidence suggests that the reactive oxygen species peroxynitrite (PN) is an important player in the pathophysiology of acute spinal cord injury (SCI). In the present study, we examined the ability of tempol, a catalytic scavenger of PN-derived free radicals, to alleviate oxidative damage, mitochondrial dysfunction and cytoskeletal degradation following a severe contusion (200 kdyn force) SCI in female Sprague-Dawley rats. PN-mediated oxidative damage in spinal cord tissue, including protein nitration, protein oxidation and lipid peroxidation was significantly reduced by acute tempol treatment (300 mg/kg, i.p. within 5 min post-injury). Injury-induced mitochondrial respiratory dysfunction, measured after 24 h in isolated mitochondria, was partially reversed by tempol along with an attenuation of oxidative damage to mitochondrial proteins. Mitochondrial dysfunction disrupts intracellular Ca(2+) homeostasis contributing to calpain-mediated axonal cytoskeletal protein (alpha-spectrin, 280 kD) degradation. Increased levels of alpha-spectrin breakdown proteins (SBDP 145 kD and 150 kD) were significantly decreased at 24 h in tempol-treated rats indicative of spinal axonal protection. However, a therapeutic window analysis showed that the axonal cytoskeletal protective effects require tempol dosing within the first hour after injury. Nevertheless, these findings are the first to support the concept that PN is an important neuroprotective target in early secondary SCI, and that there is a mechanistic link between PN-mediated oxidative compromise of spinal cord mitochondrial function, loss of intracellular Ca(2+) homeostasis and calpain-mediated proteolytic axonal damage.
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY 40536-0509, USA.
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Xiong
authors.forename: Edward D
authors.initials: ED
authors.lastname: Hall
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002154:Calpain / Q000187:drug effects / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013049:Spectrin / Q000187:drug effects / Q000378:metabolism; D013113:Spin Labels; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D005609:Free Radicals; D013113:Spin Labels; D013049:Spectrin; D030421:Peroxynitrous Acid; D002154:Calpain; C001803:tempol