Suppression of Oxidative Stress and 5-Lipoxygenase Activation by Edaravone Improves Depressive-Like Behavior after Concussion
Suppression of Oxidative Stress and 5-Lipoxygenase Activation by Edaravone Improves Depressive-Like Behavior after Concussion
复制标题
DOI：
10.1089/neu.2014.3331
复制
发表时间：
2014-10-15
影响因子：
4.2
通讯作者：
Ueba, Tetuya
中科院分区：
文献类型：
--
作者：
Higashi, Youichirou;Hoshijima, Michihiro;Ueba, Tetuya
脑脑震荡是一个严重的公众问题，并与神经精神疾病，如抑郁症有关。患有抑郁症的脑震荡患者通常会感到痛苦。然而，很少有临床前研究检查了脑震荡诱发的抑郁症，关于其药理管理的信息也很少。依达拉奉是一种自由基清除剂，可在几种神经系统疾病动物模型中发挥神经保护作用。然而，依达拉奉在脑震荡性抑郁动物模型中的有效性尚不清楚。在这项研究中，我们研究了依达拉奉是否可以预防脑震荡性抑郁。小鼠进行体重下降损伤，并在撞击后立即静脉注射依达拉奉（3.0 mg/kg）或车辆。连续磁共振成像显示大脑弥散T1和t2加权图像未见异常。在强迫游泳实验中，我们发现依达拉屈酮抑制脑震荡诱导的抑郁样行为，同时抑制海马和皮质氧化应激（OS）的增加以及海马星形胶质细胞核膜5-脂氧合酶（5-LOX）的易位。此外，烟酰胺腺嘌呤二核苷酸磷酸氧化酶抑制剂罗布麻碱和BWB70C（一种5-LOX抑制剂）可预防脑震荡小鼠海马OS，损伤后立即和24小时可预防脑震荡小鼠的抑郁样行为。此外，在撞击后立即接受1.0或3.0 mg/kg依达拉奉的小鼠中观察到依达拉奉的抗抑郁作用，而0.1 mg/kg的较低剂量则没有。这种抗抑郁作用持续到撞击后1小时，而撞击后3小时依达拉奉治疗对脑震荡引起的抑郁样行为没有影响。这些结果表明依达拉奉对脑震荡性抑郁有保护作用，这种保护作用是通过抑制OS和5-LOX易位介导的。
Brain concussions are a serious public concern and are associated with neuropsychiatric disorders, such as depression. Patients with concussion who suffer from depression often experience distress. Nevertheless, few pre-clinical studies have examined concussion-induced depression, and there is little information regarding its pharmacological management. Edaravone, a free radical scavenger, can exert neuroprotective effects in several animal models of neurological disorders. However, the effectiveness of edaravone in animal models of concussion-induced depression remains unclear. In this study, we examined whether edaravone could prevent concussion-induced depression. Mice were subjected to a weight-drop injury and intravenously administered edaravone (3.0 mg/kg) or vehicle immediately after impact. Serial magnetic resonance imaging showed no abnormalities of the cerebrum on diffusion T1- and T2-weighted images. We found that edaravone suppressed concussion-induced depressive-like behavior in the forced swim test, which was accompanied by inhibition of increased hippocampal and cortical oxidative stress (OS) and suppression of 5-lipoxygenase (5-LOX) translocation to the nuclear envelope in hippocampal astrocytes. Hippocampal OS in concussed mice was also prevented by the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin, and administration of BWB70C, a 5-LOX inhibitor, immediately and 24 h after injury prevented depressive-like behaviors in concussed mice. Further, antidepressant effects of edaravone were observed in mice receiving 1.0 or 3.0 mg/kg of edaravone immediately after impact, but not at a lower dose of 0.1 mg/kg. This antidepressant effect persisted up to 1 h after impact, whereas edaravone treatment at 3 h after impact had no effect on concussion-induced depressive-like behavior. These results suggest that edaravone protects against concussion-induced depression, and this protection is mediated by suppression of OS and 5-LOX translocation.