Neuroprotective and Functional Improvement Effects of Methylene Blue in Global Cerebral Ischemia.
Neuroprotective and Functional Improvement Effects of Methylene Blue in Global Cerebral Ischemia.
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DOI：
10.1007/s12035-015-9455-0
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发表时间：
2016-10
影响因子：
5.1
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Lu Q;Tucker D;Dong Y;Zhao N;Zhang Q
短暂性全脑缺血(GCI)导致脆弱的海马区CA1区迟发性神经细胞死亡，并导致行为障碍。脑缺血再灌注(I/R)产生过多的活性氧，在脑损伤中起关键作用。线粒体电子呼吸链是产生自由基的主要细胞来源，线粒体功能障碍对脑缺血后神经细胞死亡有重要影响。本研究旨在探讨亚甲蓝(MB)对成年雄性大鼠四支血管闭塞(4VO)GCI模型的潜在有益作用。亚甲蓝剂量为0.5 mg/kg/d，GCI后皮下植入微泵，连续7天。通过甲酚紫染色和Neun染色，我们首次发现MB显著改善了海马CA1区缺血神经元的存活。我们还发现MB具有挽救缺血所致的CA1区细胞色素c氧化酶活性下降和ATP生成的能力。进一步用MitoTracker®Red标记的分析表明，MB处理后线粒体膜电位的去极化作用明显减弱。此外，MB对CA1区caspase-3、-8和-9活性的诱导以及对TUNEL阳性细胞数量的增加均显著降低。相应地，Barnes迷宫测试显示，MB治疗组大鼠GCI后空间学习记忆能力的恶化程度明显优于缺血对照组。综上所述，我们的研究表明MB可能是一种有希望的针对短暂性全脑缺血后神经细胞死亡和认知障碍的治疗药物。
Transient global cerebral ischemia (GCI) causes delayed neuronal cell death in the vulnerable hippocampus CA1 subfield, as well as behavioral deficits. Ischemia reperfusion (I/R) produces excessive reactive oxygen species and plays a key role in brain injury. The mitochondrial electron respiratory chain is the main cellular source of free radical generation, and dysfunction of mitochondria has a significant impact on the neuronal cell death in ischemic brain. The aim of the present study is to investigate the potential beneficial effects of methylene blue (MB) in a 4-vessel occlusion (4VO) GCI model on adult male rats. MB was delivered at a dose of 0.5 mg/kg/day for 7 days, through a mini-pump implanted subcutaneously after GCI. We first found that MB significantly improved ischemic neuronal survival in hippocampal CA1 region as measured by cresyl violet staining as well as NeuN staining. We also found that MB has the ability to rescue ischemia-induced decreases of cytochrome c oxidase activity and ATP generation in CA1 region following I/R. Further analysis with labeling of MitoTracker® Red revealed that the depolarization of mitochondrial membrane potential (MMP) was markedly attenuated following MB treatment. In addition, the induction of caspase-3, -8 and -9 activities, and the increased numbers of TUNEL positive cells of CA1 region were significantly reduced by MB application. Correspondingly, Barnes maze tests showed that the deterioration of spatial learning and memory performance following GCI were significantly improved in MB-treatment group compared to ischemic control group. In summary, our study suggests that MB may be a promising therapeutic agent targeting neuronal cell death and cognitive deficits following transient global cerebral ischemia.