Nimata Masaomi, Okabe Taka-aki, Hattori Miki, Yuan Zuyi, Shioji Keisuke, Kishimoto Chiharu
Dept. of Cardiovascular Medicine, Graduate School of Medicine, Kyoto Univ., 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2514-8. doi: 10.1152/ajpheart.00661.2005. Epub 2005 Aug 12.
In this study, we tested the hypothesis that MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one; edaravone), a novel free radical scavenger, protects against acute experimental autoimmune myocarditis (EAM) in rats by the radical scavenging action associated with the suppression of cytotoxic myocardial injury. Recent evidence suggests that oxidative stress may play a role in myocarditis. We administered MCI-186 intraperitoneally at 1, 3, and 10 mg.kg(-1).day(-1) to rats with EAM for 3 wk. The results were compared with untreated rats with EAM. MCI-186 treatment did not affect hemodynamics. MCI-186 treatment (3 and 10 mg.kg(-1).day(-1)) reduced the severity of myocarditis as assessed by comparing the heart-to-body weight ratio and pathological scores. Myocardial interleukin-1beta (IL-1beta)-positive cells and myocardial oxidative stress overload with DNA damage in rats with EAM given MCI-186 treatment were significantly less compared with those of the untreated rats with EAM. In addition, MCI-186 treatment decreased not only the myocardial protein carbonyl contents but also the myocardial thiobarbituric acid reactive substance products in rats with EAM. The formation of hydroxyl radicals in MCI-186-treated heart homogenates was decreased compared with untreated heart homogenates. Furthermore, cytotoxic activities of lymphocytes of rats with EAM treated with MCI-186 were significantly lower compared with those of the untreated rats with EAM. Hydroxyl radicals may be involved in the development of myocarditis. MCI-186 protects against acute EAM in rats associated with scavenging hydroxyl free radicals, resulting in the suppression of autoimmune-mediated myocardial damage associated with reduced oxidative stress state.
在本研究中，我们验证了以下假说：新型自由基清除剂MCI-186（3-甲基-1-苯基-2-吡唑啉-5-酮；依达拉奉）通过与抑制细胞毒性心肌损伤相关的自由基清除作用，对大鼠急性实验性自身免疫性心肌炎（EAM）具有保护作用。最近的证据表明，氧化应激可能在心肌炎中起作用。我们以1、3和10 mg·kg⁻¹·d⁻¹的剂量对患有EAM的大鼠腹腔注射MCI-186，持续3周。将结果与未治疗的EAM大鼠进行比较。MCI-186治疗不影响血流动力学。通过比较心脏与体重比和病理评分评估，MCI-186治疗（3和10 mg·kg⁻¹·d⁻¹）减轻了心肌炎的严重程度。与未治疗的EAM大鼠相比 MCI-186治疗的EAM大鼠心肌白细胞介素-1β（IL-1β）阳性细胞以及伴有DNA损伤的心肌氧化应激过载明显减少。此外，MCI-186治疗不仅降低了EAM大鼠的心肌蛋白羰基含量，还降低了其心肌硫代巴比妥酸反应性物质产物。与未处理的心脏匀浆相比，MCI-186处理的心脏匀浆中羟基自由基的形成减少。此外，与未治疗的EAM大鼠相比，MCI-186治疗的EAM大鼠淋巴细胞的细胞毒性活性明显较低。羟基自由基可能参与心肌炎的发展。MCI-186通过清除羟基自由基对大鼠急性EAM具有保护作用，从而抑制与氧化应激状态降低相关的自身免疫介导的心肌损伤。
