咖啡酸、罗非昔布及其联合用药对喹啉酸诱导的行为改变及谷胱甘肽氧化还原状态紊乱的影响。
Effects of caffeic acid, rofecoxib, and their combination against quinolinic acid-induced behavioral alterations and disruption in glutathione redox status.
机构信息
Pharmacology Division, University Institute of Pharmaceutical Sciences, University Grants Commission, Centre of Advanced Study, Panjab University, Chandigarh, India.
出版信息
Neurosci Bull. 2009 Dec;25(6):343-52. doi: 10.1007/s12264-009-0513-3.
OBJECTIVE
The neuroprotective roles of cyclooxygenase (COX) and lipooxygenase (LOX) inhibitors have been well documented. Quinolinic acid (QA) is a well-known excitotoxic agent that could induce behavioral, morphological and biochemical alterations similar with symptoms of Huntington's disease (HD), by stimulating NMDA receptors. However, the exact roles of COX and LOX inhibitors in HD have not yet been explained. The present study aims to elucidate the effects of caffeic acid (a specific inhibitor for LOX), rofecoxib (a specific inhibitor for COX-2), and their combination in ameliorating QA-induced neurotoxicity in rats.
METHODS
QA was injected into the right striatum of rats to induce neurotoxicity. Caffeic acid and rofecoxib were then orally administered separately. In the combination study, caffeic acid and rofecoxib were administered together. After that, a series of behavioral assessments were conducted to determine the effects of caffeic acid and rofecoxib, respectively, and the co-effect of caffeic acid and rofecoxib, against QA-induced neurotoxicity.
RESULTS
Intrastriatal QA administration (300 nmol) not only induced a significant reduction in body weight and motor incoordination, but also altered the redox status (decreased glutathione and increased oxidized glutathione level) in striatum, as compared to the sham group. Moreover, chronic treatment with caffeic acid (5 mg/kg and 10 mg/kg, respectively, p.o.) or rofecoxib (10 mg/kg, p.o.) could significantly attenuate QA-induced behavioral alterations and restore the redox status in striatum. However, at the dose of 2.5 mg/kg, caffeic acid did not show any significant effects on these parameters in QA-treated rats. Furthermore, the combination of rofecoxib (10 mg/kg) and caffeic acid (5 mg/kg) could significantly protect against QA neurotoxicity.
CONCLUSION
The in vivo study indicates that excitotoxic injury to the brain might affect oxidant/antioxidant equilibrium by eliciting changes in glutathione. Moreover, the LOX and the COX pathways may be both involved in quinolinic-induced neurotoxicity, which provides a promising target for HD treatment.
目的
环氧化酶（COX）和脂氧合酶（LOX）抑制剂的神经保护作用已得到充分证实。喹啉酸（QA）是一种众所周知的兴奋性毒性物质，通过刺激 NMDA 受体，可诱导类似于亨廷顿病（HD）的行为、形态和生化改变。然而，COX 和 LOX 抑制剂在 HD 中的确切作用尚未得到解释。本研究旨在阐明咖啡酸（LOX 的特异性抑制剂）、罗非昔布（COX-2 的特异性抑制剂）及其组合在改善 QA 诱导的大鼠神经毒性中的作用。
方法
将 QA 注入大鼠右侧纹状体诱导神经毒性。然后分别口服给予咖啡酸和罗非昔布。在联合研究中，同时给予咖啡酸和罗非昔布。之后，进行一系列行为评估，以确定咖啡酸和罗非昔布各自的作用，以及咖啡酸和罗非昔布的共同作用对 QA 诱导的神经毒性的影响。
结果
纹状体内注射 QA（300 nmol）不仅导致体重和运动不协调明显减少，还改变了纹状体的氧化还原状态（谷胱甘肽减少，氧化谷胱甘肽水平增加），与假手术组相比。此外，慢性给予咖啡酸（分别为 5mg/kg 和 10mg/kg，po）或罗非昔布（10mg/kg，po）可显著减轻 QA 诱导的行为改变，并恢复纹状体的氧化还原状态。然而，在 2.5mg/kg 的剂量下，咖啡酸对 QA 处理大鼠的这些参数没有显示出任何显著影响。此外，罗非昔布（10mg/kg）和咖啡酸（5mg/kg）的联合应用可显著防止 QA 神经毒性。
结论
体内研究表明，脑兴奋性损伤可能通过引发谷胱甘肽变化来影响氧化还原平衡。此外，LOX 和 COX 途径可能都参与了喹啉诱导的神经毒性，为 HD 的治疗提供了一个有希望的靶点。
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