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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2.5mg/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。
Objective Epoxy and enzyme (COX) inhibitors and lipoxygenase (LOX) inhibitors have been shown to have neuroprotective effects, but little is known about their specific mechanisms. Quinolinic acid, which has an excitotoxic effect, causes symptoms similar to Huntington’s Disease (HD) by activating NMDA receptors, including various abnormalities in behavior, morphology, and biochemical levels. This study aimed to investigate the effects of caffeic acid (LOX specific inhibitor) and rofecoxib (COX specific inhibitor) and their combination on quinolinic acid-induced neurotoxicity in rats. Methods Quinolines were injected into the right striatum of rats to induce neurotoxicity. Rats are then given caffeic acid or rofecoxib daily, or both at the same time. A series of behavioral and biochemical tests were used to detect caffeic acid and rofecoxib, as well as their effects on quinolinic acid-induced behavioral changes and the improvement and repair of glutathione redox disorder. Results Injection of quinolinic acid into the striatum not only reduced body weight, induced dyskinesia, but also destroyed the balance between the redox sites in the striatum, indicating a decrease in glutathione level and an increase in oxidized glutathione level . Long-term use of caffeic acid or rofecoxib, and both can significantly reduce the quinoline acid-induced behavioral changes, restore the balance of redox levels. However, caffeic acid did not show any protective effect at a dose of 2.5 mg / kg. Conclusion The results of this experiment show that the brain excitotoxicity may affect the balance between oxidation and antioxidation by changing the level of glutathione. Both cyclooxygenase and lipoxygenase pathways are likely involved in quinolinic-induced neurotoxicity. These results provide a research target for the treatment of HD.