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

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 IIITDE-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 IIITDE-2-ImP 5+. Neurologic and histologic outcomes were assessed at 1 or 8 weeks postischemia. A single dose of Mn IIITDE-2-ImP 5+ caused a dose-dependent improvement in histologic and neurologic outcome when assessed 1 week postischemia. Mn IIITDE-2-ImP 5+ afforded preservation of brain aconitase activity at 5.5 h after reperfusion onset, consistent with its known antioxidant properties. Mn IIITDE-2-ImP 5+ also attenuated postischemic NF-κB 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 IIITDE-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.