Exogenous melatonin modulates apoptosis in the mouse brain induced by high-LET carbon ion irradiation
Exogenous melatonin modulates apoptosis in the mouse brain induced by high-LET carbon ion irradiation
复制标题
外源性褪黑素调节高LET碳离子照射诱导的小鼠脑细胞凋亡
DOI：
10.1111/j.1600-079x.2011.00917.x
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发表时间：
2012-01-01
影响因子：
10.3
通讯作者：
Wang, Zhenhua
中科院分区：
文献类型：
--
作者：
Liu, Yang;Zhang, Luwei;Wang, Zhenhua
本研究旨在探讨自由基清除剂和一般抗氧化剂褪黑素是否在信号转导途径水平上调节碳离子诱导的小鼠脑细胞凋亡。将幼龄昆明种小鼠随机分为5组：对照组、照射组和3种褪黑素(1、5、10 mg/kg/d，共5天)组。加照射组。对4Gy单剂量照射后12小时小鼠脑内氧化状态、细胞凋亡、线粒体膜电位以及促凋亡和抗凋亡蛋白水平进行了研究。照射组小鼠氧化应激和细胞凋亡显著增加(TUNEL阳性)，并伴有Bax、细胞色素c、半胱氨酸天冬氨酸氨基转移酶-3的激活表达和β-M水平的降低。补充褪黑素能更好地减轻辐射所致的氧化损伤，提高抗氧化酶(超氧化物歧化酶和过氧化氢酶)活性和总抗氧化能力。此外，服用褪黑素显著提高了Nrf2的表达，Nrf2调节氧化还原平衡和应激。此外，褪黑素治疗还可减轻细胞凋亡率，维持线粒体活力，减少线粒体细胞色素c的释放，下调Bax/Bcl2比值和caspase-3水平，从而抑制辐射诱导线粒体凋亡途径激活的重要步骤。因此，我们认为褪黑素的抗凋亡作用可能至少部分是通过消除碳离子诱导的氧化应激，增加Nrf2的表达和抗氧化酶活性来实现的。
The aim of this study was to investigate whether melatonin, a free radical scavenger and a general antioxidant, regulates the brain cell apoptosis caused by carbon ions in mice at the level of signal transduction pathway. Young Kun-Ming mice were divided into five groups: control group, irradiation group and three melatonin (1, 5, and 10 mg/kg daily for 5 days i.p.) plus irradiation-treated groups. An acute study was carried out to determine oxidative status, apoptotic cells, and mitochondrial membrane potential (??m) as well as pro- and anti-apoptotic protein levels in a mouse brain 12 hr after irradiation with a single dose of 4 Gy. In irradiated mice, a significant rise in oxidative stress and apoptosis (TUNEL positive) was accompanied by activated expression of Bax, cytochrome c, caspase-3, and decreased ??m level. Melatonin supplementation was better able to reduce irradiation-induced oxidative damage marked by carbonyl or malondialdehyde content, and stimulate the antioxidant enzyme activities (superoxide dismutase and catalase) together with total antioxidant capacity. Moreover, administration with melatonin pronouncedly elevated the expression of Nrf2 which regulates redox balance and stress. Furthermore, melatonin treatment mitigated apoptotic rate, maintained ??m, diminished cytochrome c release from mitochondria, down-regulated Bax/Bcl-2 ratio and caspase-3 levels, and consequently inhibited the important steps of irradiation-induced activation of mitochondrial pathway of apoptosis. Thus, we propose that the anti-apoptotic action with the alterations in apoptosis regulator provided by melatonin may be responsible at least in part for its antioxidant effect by the abolishing of carbon ioninduced oxidative stress along with increasing Nrf2 expression and antioxidant enzyme activity.