Neuroprotective effects of thymoquinone against transient forebrain ischemia in the rat hippocampus
Neuroprotective effects of thymoquinone against transient forebrain ischemia in the rat hippocampus
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DOI：
10.1016/j.ejphar.2006.05.046
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发表时间：
2006-08-14
影响因子：
5
通讯作者：
Nagi, Mahmoud N.
中科院分区：
文献类型：
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作者：
Al-Majed, Abdulhakeem A.;Al-Omar, Fadhel A.;Nagi, Mahmoud N.
越来越多的证据表明，在实验性脑缺血模型中，氧化应激在脑损伤中起着重要作用。百里香酚是黑种草种子挥发油的主要成分，据报道具有很强的抗氧化性。因此，本研究旨在探讨百里酚对短暂性前脑缺血所致大鼠海马神经元损伤的保护作用。将大鼠随机分为5组：对照组、假手术组、缺血组、百里酚组和缺血+百里酚组。结扎双侧颈总动脉10min，再灌流7d，建立短暂性前脑缺血模型。心肌缺血前5天给予胸腺醌(5 mg/kg/d)，持续至再灌注期。处死动物，分离脑组织进行组织病理学检查。海马区组织还用于测定脂质过氧化的终产物丙二醛水平、关键抗氧化剂谷胱甘肽(GSH)水平以及抗氧化酶过氧化氢酶和超氧化物歧化酶(SOD)的活性。用抗坏血酸铁体外诱导大鼠海马匀浆中的非酶脂质过氧化反应，观察了胸腺酚及其代谢产物胸腺氢二酚对其的抑制作用。组织病理学观察显示大鼠前脑缺血再灌流后7d，海马区CA1区神经细胞明显死亡(77%的细胞丢失)。此外，与对照组或假手术组相比，大鼠前脑缺血再灌注后海马区组织中丙二醛含量显著升高，GSH含量、过氧化氢酶和超氧化物歧化酶活性显著降低，显示前脑缺血再灌注氧化损伤。百里酚预处理减轻了前脑缺血所致的神经元损伤，表现为显著减少海马神经细胞的死亡数量(百里酚组为24%，缺血组为77%，P<；0.001)，证实了百里酚组在缺血再灌注损伤中的保护作用。此外，百里香酚可降低缺血大鼠脑内丙二醛含量升高的水平，使GSH含量、过氧化氢酶和超氧化物歧化酶活性恢复到正常水平。胸腺二酚和胸腺氢二酚可抑制抗坏血酸铁诱导的海马匀浆中非酶脂质过氧化作用。百里香酚和百里香对苯二酚的IC50分别为12mM和3mM。这表明百里香酚及其代谢物的保护作用涉及增强对氧化应激的抵抗力。结论：百里香酚对大鼠短暂性前脑缺血所致的大鼠海马区损伤有保护作用。这种惊人的保护作用使百里酚成为一种很有希望的药物，用于脑缺血等神经退行性病变的病理研究。(C)2006爱思唯尔B.V.保留所有权利。
Increasing evidence demonstrates that oxidative stress plays an important role in brain injury in experimental models of brain ischemia. Thymoquinone, the main constituents of the volatile oil from Negella saliva seeds, is reported to possess strong antioxidant properties. Hence, the present study was undertaken to evaluate the neuroprotective effect of thymoquinone against transient forebrain ischemia-induced neuronal damage in the rat hippocampus. Rats were divided randomly into five groups: control, sham, ischemia, thymoquinone and ischemia + thymoquinone. Transient forebrain ischemia was induced with bilateral occlusion of both common carotid arteries for 10 min followed by 7 days of reperfasion. Thymoquinone was administered (5 mg/kg/day p.o.) 5 days before ischemia and continued during the reperfusion time. Animals were sacrificed, and brain tissues were isolated for histopathological examination. Hippocampal tissues were also used for determination of malondialdehyde levels, an end product of lipid peroxidation; glutathione (GSH) levels, a key antioxidant and the activities of the antioxidant enzymes catalase and superoxide dismutase (SOD). Thymoquinone and its metabolite thymohydroquinone were tested as inhibitors of the in vitro non-enzymatic lipid peroxidation induced by iron-ascorbate in the hippocampal homogenate. Forebrain ischemia-reperftision neural injury in rats was demonstrated by histopathological observation, which revealed significant neural cell death in the hippocarnpus CA1 area 7 days postischemia (77% cell loss). Additionally, forebrain ischemia-reperfusion oxidative injury in rats was demonstrated by a significant increase in malondialdehyde and a significant decrease in GSH contents, catalase and SOD activities in the hippocampal tissue compared to the control or sham-operated groups. Pretreatment of thymoquinone attenuated forebrain ischemia-induced neuronal damage manifested by significantly decreasing the number of dead hippocampal neuronal cells (24% in thymoquinone-treated versus 77% for ischemia, P < 0.001), which confirm the protective role of thymoquinone in ischemia-reperfusion injury. Also, pretreatment of ischemic rats with thymoquinone decreased the elevated levels of malondialdehyde and increased GSH contents, catalase and SOD activities to normal levels. Thymoquinone and thymohydroquinone inhibited the in vitro non-enzymatic lipid peroxidation in hippocampal homogenate induced by iron-ascorbate. The IC50 for thymoquinone and thymohydroquinone were found to be 12 and 3 mu M respectively. This suggests that the protection of thymoquinone and its metabolite involve increased resistance to oxidative stress. In conclusion, thymoquinone is effective in protecting rats against transient forebrain ischemia-induced damage in the rat hippocampus. This spectacular protection makes thymoquinone a promising agent in pathologies implicating neurodegenaration such as cerebral ischemia. (c) 2006 Elsevier B.V All rights reserved.