The Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
Free Radic Biol Med. 2009 Oct 1;47(7):917-23. doi: 10.1016/j.freeradbiomed.2009.05.039. Epub 2009 Jul 22.
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.
持续的氧化应激是局灶性脑缺血的已知后果。本研究探讨了单次剂量或持续输注氧化还原调节 MnPorphyrin Mn(III)TDE-2-ImP(5+)对大鼠大脑中动脉闭塞 (MCAO) 后结果的影响。正常体温大鼠接受 90 分钟 MCAO 后再灌注 90 分钟，然后用单次脑室注射 Mn(III)TDE-2-ImP(5+)进行治疗。在缺血后 1 或 8 周评估神经和组织学结果。在缺血后 1 周评估时，单次剂量的 Mn(III)TDE-2-ImP(5+)导致组织学和神经学结果呈剂量依赖性改善。Mn(III)TDE-2-ImP(5+)在再灌注开始后 5.5 小时即可维持脑乌头酸酶活性，这与其已知的抗氧化特性一致。Mn(III)TDE-2-ImP(5+)还可减轻缺血后 NF-κB 的激活。当大鼠允许在缺血后 8 周存活时，对脑梗死面积和神经功能的影响完全消失。相比之下，缺血后 1 周持续的脑室内 Mn(III)TDE-2-ImP(5+)输注可导致缺血后 8 周时脑梗死面积和神经功能缺损持续和实质性减少。为了持久改善短暂性局灶性缺血损伤后的神经和组织学结果，对缺血后氧化应激的药物调节可能需要持续干预。
