Doxorubicin-induced central nervous system toxicity and protection by xanthone derivative of Garcinia mangostana.
Doxorubicin-induced central nervous system toxicity and protection by xanthone derivative of Garcinia mangostana.
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DOI：
10.1016/j.neuroscience.2010.11.007
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发表时间：
2011-02-23
期刊：
影响因子：
3.3
通讯作者：
St Clair, D. K.
中科院分区：
文献类型：
--
作者：
Tangpong, J.;Miriyala, S.;Noel, T.;Sinthupibulyakit, C.;Jungsuwadee, P.;St Clair, D. K.
阿霉素（Dox）是一种有效的广谱化疗药物，在世界各地使用。尽管它有效，但它有广泛的毒副作用，其中许多很可能是由于其固有的促氧化活性。据报道，Dox对包括脑组织在内的正常组织有毒性作用。本研究测试了山竹黄酮衍生物对dox诱导的神经元毒性的保护作用。山酮可阻止阿霉素引起单核细胞肿瘤坏死因子- α (tnf - α)水平升高。我们发现，在给药前给予小鼠山酮可抑制脑组织中羰基蛋白、硝基酪氨酸和4-羟基-2 ' -壬烯醛(4HNE)-内合蛋白。与对照组相比，dox处理小鼠的促凋亡蛋白p53、Bax和抗凋亡蛋白Bcl-xL水平显著升高。与凋亡标志物的增加一致，dox处理小鼠的caspase-3活性和tunel阳性细胞水平也增加。经口山酮预处理可抑制dox诱导的所有损伤指标的升高。综上所述，结果表明，克山酮通过抑制dox介导的循环TNFα的增加，至少在一定程度上阻止了dox诱导的中枢神经系统毒性。因此，山酮是预防由活性氧产生的全身效应的良好候选抗癌药物。
Doxorubicin (Dox) is a potent, broad-spectrum chemotherapeutic drug used around the world. Despite its effectiveness, it has a wide range of toxic side effects, many of which most likely result from its inherent pro-oxidant activity. It has been reported that Dox has toxic effects on normal tissues, including brain tissue. The present study tested the protective effect of a xanthone derivative of Garcinia Mangostana against Dox-induced neuronal toxicity. Xanthone can prevent Dox from causing mononuclear cells to increase the level of tumor necrosis factor-alpha (TNFα). We show that xanthone given to mice before Dox administration suppresses protein carbonyl, nitrotyrosine and 4-hydroxy-2′-nonenal (4HNE)-adducted proteins in brain tissue. The levels of the pro-apoptotic proteins p53 and Bax and the anti-apoptotic protein Bcl-xL were significantly increased in Dox-treated mice compared with the control group. Consistent with the increase of apoptotic markers, the levels of caspase-3 activity and TUNEL-positive cells were also increased in Dox-treated mice. Pretreatment with xanthone suppressed Dox-induced increases in all indicators of injury tested. Together, the results suggest that xanthone prevents Dox-induced central nervous system toxicity, at least in part, by suppression of Dox-mediated increases in circulating TNFα. Thus, xanthone is a good candidate for prevention of systemic effects resulting from reactive oxygen generating anticancer therapeutics.
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