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: 环氧和酶(COX)抑制剂和脂肪氧化酶(LOX)抑制剂已被证实具有神经保护作用, 但对其具体机制目前研究甚少。 喹啉酸具有兴奋毒性作用, 通过激活NMDA 受体, 引起类似于亨廷顿舞蹈症 (Huntington’s Disease, HD) 的症状, 包括行为、 形态以及生化水平上的各种异常。 本研究旨在探讨咖啡酸(LOX特异性抑制剂)和罗非考昔(COX特异性抑制剂)各自以及两者连用对喹啉酸引起的大鼠神经毒性的改善和修复作用。
方法: 在大鼠右侧纹状体内注射喹啉酸, 诱导神经毒性。 随后每天给大鼠口服咖啡酸或罗非考昔, 或两者同时服用。 用一系列行为学及生化检测方法检测咖啡酸和罗非考昔, 以及两者连用对喹啉酸诱导的大鼠行为变化及谷胱甘肽氧化还原紊乱的改善和修复作用。
结果: 在纹状体注射喹啉酸不仅能降低大鼠体重, 引起运动失调, 而且能破坏纹状体内氧化还原间的平衡, 表现为谷胱甘肽水平降低, 以及氧化谷胱甘肽水平升高。 长期服用咖啡酸或罗非考昔, 以及两者连用都能显著减轻喹啉酸引起的行为变化, 修复氧化还原水平的平衡。 而当剂量为2.5 mg/kg 时, 咖啡酸未表现出任何保护作用。
结论: 本实验结果表明, 大脑的兴奋性中毒有可能通过改变谷胱甘肽的水平影响氧化与抗氧化间的平衡。 环氧合酶和脂肪氧化酶通路都可能参与了喹啉酸诱导的神经毒性过程。 这些结果为治疗HD提供了研究靶点。