Glutathione elevation by γ-glutamyl cysteine ethyl ester as a potential therapeutic strategy for preventing oxidative stress in brain mediated by in vivo administration of adriamycin:: Implication for chemobrain
Glutathione elevation by γ-glutamyl cysteine ethyl ester as a potential therapeutic strategy for preventing oxidative stress in brain mediated by in vivo administration of adriamycin:: Implication for chemobrain
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DOI：
10.1002/jnr.21158
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发表时间：
2007-02-15
影响因子：
4.2
通讯作者：
Butterfield, D. Allan
中科院分区：
文献类型：
--
作者：
Joshi, Gururaj;Hardas, Sarita;Butterfield, D. Allan
用于治疗实体瘤的癌症化疗药物阿霉素（ADR）在心脏和大脑中产生的氧化应激已得到充分证实。乳腺癌患者长期接受ADR治疗会导致心血管病症状。认知功能障碍虽然不太为人所知，但却越来越多地被记录在案。化疗后，自由基介导的氧化应激已被报道在心脏和大脑。我们最近发现，从腹腔注射（i.p）ADR的小鼠中分离的脑中蛋白质氧化和脂质过氧化反应显著增加。ADR的全身给药还诱导肿瘤坏死因子-α（TNF-α），导致脑中活性氧（ROS）和活性氮（RNS）的产生。循环TNF还引起线粒体功能障碍，导致脑中的凋亡途径。诱导型一氧化氮合酶也在ADR诱导的TNIF介导的神经毒性中发挥作用。此外，我们之前发现从注射ADR的小鼠中分离的脑中谷胱甘肽（GSH）水平显著降低，沿着多药耐药蛋白-1（MRIP-1）、谷胱甘肽-S-转移酶（GST）、谷胱甘肽过氧化物酶（GPx）和谷胱甘肽还原酶（GR）的表达增加。脑GST活性显著降低。本研究旨在验证这一假设，即通过升高脑GSH水平，脑将在注射ADR的小鼠中免受氧化应激。在注射ADR（20 mg/kg体重）前4小时腹膜内注射γ-谷氨酰半胱氨酸乙酯（GCEE）（谷胱甘肽的前体），导致随后分离的小鼠脑中的蛋白质氧化和脂质过氧化反应与从注射ADR但未注射GCEE的小鼠中分离的脑相比显著降低。GSH水平恢复到从盐水注射小鼠分离的脑的水平。此外，与先前注射盐水的注射ADR的小鼠的脑分离的脑相比，先前注射GCEE的注射ADR的小鼠的脑分离的GST的酶活性增加。这些结果进行了讨论，就潜在的药物预防脑认知功能障碍的患者接受ADR化疗。(c)2006 Wiley-Liss，Inc.
Oxidative stress in heart and brain by the cancer chemotherapeutic drug adriamycin (ADR), used for treating solid tumors, is well established. Long-term treatment with ADR in breast cancer patients has led to symptoms of cardiornyopathy. Less well recognized, but increasingly well documented, is cognitive dysfunction. After chemotherapy, free radical-mediated oxidative stress has been reported in both heart and brain. We recently showed a significant increase in protein oxidation and lipid peroxidation in brain isolated from mice injected intraperitonially (i.p) with ADR. Systemic administration of ADR also induces tumor necrosis factor-alpha (TNF-alpha), which leads to production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in brain. Circulating TNF also causes mitochondrial dysfunction, leading to apoptotic pathways in brain. Inducible nitric oxide synthase also plays a role in ADR-induced TNIF-mediated neurotoxicity. In addition, we previously showed a significant decrease in glutathione (GSH) levels in brain isolated from ADR injected mice, along with increased expression of multidrug-resistant protein-1 (MRIP-1), glutathione-S-transferase (GST), glutathione peroxidase (GPx), and glutathione reductase (GR). There was a significant decrease in activity of brain GST The present study was designed to test the hypothesis that, by elevating brain levels of GSH, the brain would be protected against oxidative stress in ADR-injected mice. gamma-Glutamyl cysteine ethyl ester (GCEE), a precursor of glutathione, injected i.p. (150 mg/kg body weight) 4 hr prior ADR injection (20 mg/kg body weight) led to significantly decreased protein oxidation and lipid peroxidation in subsequently isolated mice brain compared with brain isolated from ADR-injected mice without GCEE. The GSH levels were restored to the level of brain isolated from saline-injected mice. Furthermore, the enzyme activity of GST was increased in brain isolated from ADR-injected mice previously injected with GCEE compared with the brain isolated from ADR-injected mice previously injected with saline. These results are discussed with regard to potential pharmacological prevention of brain cognitive dysfunction in patients receiving ADR chemotherapy. (c) 2006 Wiley-Liss, Inc.