Neuroprotective effects of tempol, a catalytic scavenger of peroxynitrite-derived free radicals, in a mouse traumatic brain injury model

J Cereb Blood Flow Metab. 2008 Jun;28(6):1114-26. doi: 10.1038/jcbfm.2008.10. Epub 2008 Mar 5.

Abstract

We examined the ability of tempol, a catalytic scavenger of peroxynitrite (PN)-derived free radicals, to reduce cortical oxidative damage, mitochondrial dysfunction, calpain-mediated cytoskeletal (alpha-spectrin) degradation, and neurodegeneration, and to improve behavioral recovery after a severe (depth 1.0 mm), unilateral controlled cortical impact traumatic brain injury (CCI-TBI) in male CF-1 mice. Administration of a single 300 mg/kg intraperitoneal dose of tempol 15 mins after TBI produced a complete suppression of PN-mediated oxidative damage (3-nitrotyrosine, 3NT) in injured cortical tissue at 1 h after injury. Identical tempol dosing maintained respiratory function and attenuated 3NT in isolated cortical mitochondria at 12 h after injury, the peak of mitochondrial dysfunction. Multiple dosing with tempol (300 mg/kg intraperitoneally at 15 mins, 3, 6, 9, and 12 h) also suppressed alpha-spectrin degradation by 45% at its 24 h post-injury peak. The same dosing regimen improved 48 h motor function and produced a significant, but limited (17.4%, P<0.05), decrease in hemispheric neurodegeneration at 7 days. These results are consistent with a mechanistic link between PN-mediated oxidative damage to brain mitochondria, calpain-mediated proteolytic damage, and neurodegeneration. However, the modest neuroprotective effect of tempol suggests that multitarget combination strategies may be needed to interfere with posttraumatic secondary injury to a degree worthy of clinical translation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Brain Injuries / drug therapy*
  • Brain Injuries / metabolism*
  • Calpain / metabolism
  • Catalysis
  • Cyclic N-Oxides / pharmacology
  • Cyclic N-Oxides / therapeutic use*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Free Radicals / metabolism*
  • Male
  • Mice
  • Mitochondria / metabolism
  • Oxidative Stress / drug effects
  • Peroxynitrous Acid / metabolism*
  • Spectrin / metabolism
  • Spin Labels

Substances

  • Cyclic N-Oxides
  • Free Radicals
  • Spin Labels
  • Spectrin
  • Peroxynitrous Acid
  • Calpain
  • tempol