Long-term neuroprotection from a potent redox-modulating metalloporphyrin in the rat

Free Radic Biol Med. 2009 Oct 1;47(7):917-23. doi: 10.1016/j.freeradbiomed.2009.05.039. Epub 2009 Jul 22.

Abstract

Sustained oxidative stress is a known sequel to focal cerebral ischemia. This study examined the effects of treatment with a single dose or sustained infusion of the redox-modulating MnPorphyrin Mn(III)TDE-2-ImP(5+) on outcome from middle cerebral artery occlusion (MCAO) in the rat. Normothermic rats were subjected to 90 min MCAO followed by 90 min reperfusion and then were treated with a single intracerebroventricular dose of Mn(III)TDE-2-ImP(5+). Neurologic and histologic outcomes were assessed at 1 or 8 weeks postischemia. A single dose of Mn(III)TDE-2-ImP(5+) caused a dose-dependent improvement in histologic and neurologic outcome when assessed 1 week postischemia. Mn(III)TDE-2-ImP(5+) afforded preservation of brain aconitase activity at 5.5 h after reperfusion onset, consistent with its known antioxidant properties. Mn(III)TDE-2-ImP(5+) also attenuated postischemic NF-kappaB activation. Evidence for effects on cerebral infarct size and neurologic function had completely dissipated when rats were allowed to survive for 8 weeks postischemia. In contrast, a 1-week continuous intracerebroventricular Mn(III)TDE-2-ImP(5+) infusion caused persistent and substantive reduction in both cerebral infarct size and neurologic deficit at 8 weeks postischemia. Pharmacologic modulation of postischemic oxidative stress is likely to require sustained intervention for enduring efficacy in improving neurologic and histologic outcome from a transient focal ischemic insult.

Publication types

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

MeSH terms

  • Aconitate Hydratase / metabolism
  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Infarction, Middle Cerebral Artery / drug therapy*
  • Male
  • Metalloporphyrins / pharmacology*
  • Metalloporphyrins / therapeutic use
  • NF-kappa B / metabolism
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / drug effects
  • Rats
  • Rats, Wistar
  • Treatment Outcome

Substances

  • Metalloporphyrins
  • Mn(III) tetrakis(N,N'-diethylimidazolium-2-yl)porphyrin
  • NF-kappa B
  • Neuroprotective Agents
  • manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin
  • Aconitate Hydratase