巴西苏木红素对脑缺血再灌注损伤的作用及血管活性研究
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摘要
脑缺血疾病是一种发病率、死亡率高,愈后合并症和后遗症发生普遍的疾病。目前,针对于治疗脑缺血疾病药物的研究进展缓慢,可用于临床的安全、有效的药物种类十分有限。因此,寻找可以用于帮助疾病恢复的潜力化合物,具有很好科研意义和应用价值。巴西苏木红素是来自于中药材苏木的酚类单体化合物,本文对该化合物的活性研究主要围绕巴西苏木红素对脑缺血再灌注损伤的保护作用以及巴西苏木红素的血管调节活性两部分进行。
论文从体外和体内两个水平对巴西苏木红素对抗缺血损伤的活性进行了评价。体外实验中建立了Neuro-2a细胞的缺糖缺氧模型,采用MTT存活率和乳酸脱氢酶逸漏率两个指标对巴西苏木红素的活性进行了评价。体内实验中选取了暂时性局灶型大鼠中动脉缺血模型,通过对脑组织梗塞体积、神经行为学分数、能荷水平以及MDA水平几个指标对巴西苏木红素的作用进行评价。在机制研究中,采用RT-PCR的方法分析了巴西苏木红素对中动脉暂时性缺血大鼠脑组织以及LPS诱导的BV2小胶质细胞中三种前炎性因子(TNF-α, IL-6, IL-1β)表达的影响,以及对LPS诱导的BV2小胶质细胞和RAW264.7细胞的一氧化氮以及一氧化氮合酶水平的影响。此外,本论文还利用大鼠胸主动脉血管环实验,研究了巴西苏木红素对血管张力的影响。
研究结果表明:巴西苏木红素对缺糖缺氧损伤的Neuro-2细胞具有一定的保护作用,可以提高细胞的存活率并降低细胞乳酸脱氢酶的逸漏率;巴西苏木红素可以对抗大鼠脑缺血再灌注损伤,表现为脑缺血区域坏死体积的减少和神经行为学功能的恢复,同时巴西苏木红素也可以帮助脑组织能荷的恢复和MDA水平的降低;使用巴西苏木红素治疗后,脑缺血大鼠的脑组织中两种炎性因子即TNF-α和IL-6的mRNA水平出现了明显的降低,在LPS诱导的BV2细胞内,TNF-α和IL-6的mRNA水平也得到了相一致的结果,而且,巴西苏木红素对LPS诱导的一氧化氮合酶的表达和一氧化氮的释放也有抑制作用。以上结果提示对炎症反应的抑制作用可能是巴西苏木红素对抗脑缺血损伤的作用机制之一;在血管活性的研究中发现,巴西苏木红素具有收缩血管的活性,调节细胞外钙离子的内流、提高细胞对钙离子的敏感性、促使血管平滑肌肌球蛋白轻链磷酸化是其作用发挥的可能机制。
Cerebral ischemia is a disease with high morbidity, mortality and is associated with frequent complications and sequela for survivors. Currently, drugs which are effective and safe for the cerebral ischemia disease are far from requirement in clinic. However the drug research and development for cerebral ischemia is still in slow progress. Therefore, it is of great scientific and practical value to find the potential compounds which can help the recovery of the disease. Brazilein is a phenolic compound seperated from the traditional Chinese medicine Caesalpinia sappan L.. In this dissertation, the activities of the compound were investigated, mainly on the content of its protective effect against cerebral ischemia-reperfusion injury and its vasoactivity.
The activities of brazilein were evaluated both in vitro and in vivo. In vitro, the oxygen-glucose deprived model of neuro-2a cells was established; MTT survival and the lactate dehydrogenase efflux level were determined. In vivo, the rat transient focal cerebral ischemia model was selected and infarction volume, neurological scores, the energy charge level and level of MDA were used for evaluation. For the mechanism studies, the mRNA levels of three pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) were determined by RT-PCR method both in rat middle artery occlusion model and in LPS-induced BV2 microglial cells model. The level of nitric oxide and nitric oxide synthase in LPS-induced BV2 microglial cells and RAW264.7 cells was also analyzed. In addition, the vaso-activities of brazilein were investigated using rat arterial rings in vitro.
According to the results, we conclude that: brazilein can protect the neuron-2a cells against oxygen-glucose deprived injury for the higher MTT survival and the lower lactate dehydrogenase efflux level; brazilein can protect rats against cerebral ischemia reperfusion injury in terms of reduction of infarction volume, improvement in neurological scores, recovery of energy charge and decrease of MDA level; the mRNA level of two pro-inflammatory cytokinses, TNF-αand IL-6 showed significant reduction both in the ischemic brain of rats and in LPS-induced BV2 cells when treated with brazilein; both the release of nitric oxide and the expression of the inducible nitric oxide synthase was suppressed in LPS-induced BV2 microglial model by brazilein,these results indicated that the anti-inflammatory effect of brazilein should be one of the contributive mechanisms of its neuroprotective function; in the vaso-avtivity researches, we found brazilein can induce contraction of rat aorta and increasing extracellular Ca~(2+) influx, stimulating cellular Ca~(2+) sensitivity and promoting the phosphorylation of myosin light chain of smooth muscle cells were believed to be the possible mechanisms for the contractile processes.
论文从体外和体内两个水平对巴西苏木红素对抗缺血损伤的活性进行了评价。体外实验中建立了Neuro-2a细胞的缺糖缺氧模型,采用MTT存活率和乳酸脱氢酶逸漏率两个指标对巴西苏木红素的活性进行了评价。体内实验中选取了暂时性局灶型大鼠中动脉缺血模型,通过对脑组织梗塞体积、神经行为学分数、能荷水平以及MDA水平几个指标对巴西苏木红素的作用进行评价。在机制研究中,采用RT-PCR的方法分析了巴西苏木红素对中动脉暂时性缺血大鼠脑组织以及LPS诱导的BV2小胶质细胞中三种前炎性因子(TNF-α, IL-6, IL-1β)表达的影响,以及对LPS诱导的BV2小胶质细胞和RAW264.7细胞的一氧化氮以及一氧化氮合酶水平的影响。此外,本论文还利用大鼠胸主动脉血管环实验,研究了巴西苏木红素对血管张力的影响。
研究结果表明:巴西苏木红素对缺糖缺氧损伤的Neuro-2细胞具有一定的保护作用,可以提高细胞的存活率并降低细胞乳酸脱氢酶的逸漏率;巴西苏木红素可以对抗大鼠脑缺血再灌注损伤,表现为脑缺血区域坏死体积的减少和神经行为学功能的恢复,同时巴西苏木红素也可以帮助脑组织能荷的恢复和MDA水平的降低;使用巴西苏木红素治疗后,脑缺血大鼠的脑组织中两种炎性因子即TNF-α和IL-6的mRNA水平出现了明显的降低,在LPS诱导的BV2细胞内,TNF-α和IL-6的mRNA水平也得到了相一致的结果,而且,巴西苏木红素对LPS诱导的一氧化氮合酶的表达和一氧化氮的释放也有抑制作用。以上结果提示对炎症反应的抑制作用可能是巴西苏木红素对抗脑缺血损伤的作用机制之一;在血管活性的研究中发现,巴西苏木红素具有收缩血管的活性,调节细胞外钙离子的内流、提高细胞对钙离子的敏感性、促使血管平滑肌肌球蛋白轻链磷酸化是其作用发挥的可能机制。
Cerebral ischemia is a disease with high morbidity, mortality and is associated with frequent complications and sequela for survivors. Currently, drugs which are effective and safe for the cerebral ischemia disease are far from requirement in clinic. However the drug research and development for cerebral ischemia is still in slow progress. Therefore, it is of great scientific and practical value to find the potential compounds which can help the recovery of the disease. Brazilein is a phenolic compound seperated from the traditional Chinese medicine Caesalpinia sappan L.. In this dissertation, the activities of the compound were investigated, mainly on the content of its protective effect against cerebral ischemia-reperfusion injury and its vasoactivity.
The activities of brazilein were evaluated both in vitro and in vivo. In vitro, the oxygen-glucose deprived model of neuro-2a cells was established; MTT survival and the lactate dehydrogenase efflux level were determined. In vivo, the rat transient focal cerebral ischemia model was selected and infarction volume, neurological scores, the energy charge level and level of MDA were used for evaluation. For the mechanism studies, the mRNA levels of three pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) were determined by RT-PCR method both in rat middle artery occlusion model and in LPS-induced BV2 microglial cells model. The level of nitric oxide and nitric oxide synthase in LPS-induced BV2 microglial cells and RAW264.7 cells was also analyzed. In addition, the vaso-activities of brazilein were investigated using rat arterial rings in vitro.
According to the results, we conclude that: brazilein can protect the neuron-2a cells against oxygen-glucose deprived injury for the higher MTT survival and the lower lactate dehydrogenase efflux level; brazilein can protect rats against cerebral ischemia reperfusion injury in terms of reduction of infarction volume, improvement in neurological scores, recovery of energy charge and decrease of MDA level; the mRNA level of two pro-inflammatory cytokinses, TNF-αand IL-6 showed significant reduction both in the ischemic brain of rats and in LPS-induced BV2 cells when treated with brazilein; both the release of nitric oxide and the expression of the inducible nitric oxide synthase was suppressed in LPS-induced BV2 microglial model by brazilein,these results indicated that the anti-inflammatory effect of brazilein should be one of the contributive mechanisms of its neuroprotective function; in the vaso-avtivity researches, we found brazilein can induce contraction of rat aorta and increasing extracellular Ca~(2+) influx, stimulating cellular Ca~(2+) sensitivity and promoting the phosphorylation of myosin light chain of smooth muscle cells were believed to be the possible mechanisms for the contractile processes.
引文
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