旋覆花素对阿尔茨海默病的干预及其机制的实验研究
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摘要
阿尔茨海默病(Alzheimer’s disease, AD)是一种常见的老年神经变性疾病,临床上表现为进行性认知功能障碍和精神异常。随着世界人口老龄化程度不断提高,AD的发病率也不断上升,影响到世界范围2~3千万人口,现已成为老年人的常见病之一。其病理特征为:神经元外β-淀粉样蛋白(Aβ)聚集形成老年斑,神经元内tau蛋白异常聚集形成神经原纤维缠结(neurofibrillary tangle, NFT),脑皮质、海马胆碱能神经元及其突触大量丢失,累及皮层动脉和小动脉出现血管淀粉样变性。AD的病因至今尚未明了,随着近年对AD发病机制的研究,认识到脑内慢性炎症反应可能是其重要病理特征之一,Aβ和NFT等抗原物质激活脑内的小胶质细胞和星形胶质细胞,引起过度的免疫炎症反应,造成信号转导通路发生紊乱,导致神经细胞死亡,表现为学习、记忆等认知功能和日常行为障碍,最终发展为痴呆。因此,寻找抑制AD过度炎症反应、抑制前炎症因子的过表达、抑制β-淀粉样蛋白沉积药物,可能成为AD的有效治疗手段。
单味中药的某一类化学成分药理作用明确,疗效稳定,毒副作用小,符合当前的医疗市场要求,对防治老年痴呆有着良好的市场前景。欧亚旋覆花(Inula Britannica)是一种传统的中草药,其化学成分有40多种,旋覆花内酯(1-o-acetylbritannilactone, ABL)是从欧亚旋覆花的氯仿提取物中分离出的有效单体成分,体外证实旋覆花内酯通过抑制NF-κB的激活而消除LPS诱导的炎症相关基因如环加氧酶(cyclo-oxygenase-2,COX-2)和诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)等的表达而发挥抑制巨噬细胞活化和抗炎作用。基于AD是一种慢性炎症性疾病,旋覆花素是旋覆花单体有效成分的特定组合,本研究通过观察旋覆花素对Aβ诱导的AD模型大鼠的干预效应,探讨其作用机制,旨在确定该有效部位的药用价值和作用途径。
1旋覆花素对AD模型大鼠脑海马组织COX-2,iNOS基因表达的影响
脑内慢性炎症反应是AD的重要病理特征,多种炎症因子能促进COX-2和iNOS的表达,COX-2和iNOS及其催化产物又可促进炎症的进一步发展,直接或间接引起神经元的死亡。本实验采用免疫组织化学及Western blot方法,分别观察旋覆花素对AD模型大鼠脑海马组织炎性基因COX-2,iNOS表达的影响。实验结果如下:
1.1旋覆花素对AD模型大鼠脑海马组织COX-2基因表达的影响作为炎症相关基因,COX-2广泛参与机体的炎症反应,本实验观察了旋覆花素对COX-2表达的影响。对照组海马组织COX-2阳性染色细胞数量少,且几乎不着色;模型组海马组织COX-2阳性染色细胞数量多,着色深;旋覆花素给药组大鼠COX-2阳性染色细胞数量较模型组减少,着色较浅,但仍比对照组数量多,着色深。Western blot显示,对照组海马组织COX-2表达量低,模型组海马组织表达量显著增高,给予旋覆花素治疗后,大鼠脑海马组织COX-2表达量明显下降。以上结果提示旋覆花素可以抑制Aβ诱导的AD模型大鼠脑海马组织的COX-2基因的表达。
1.2旋覆花素对AD模型大鼠脑海马组织iNOS基因表达的影响激活的小胶质细胞活化iNOS产生大量具有神经毒性的NO,导致神经元死亡。本实验观察了旋覆花素对iNOS表达的影响。对照组海马组织iNOS阳性染色细胞数量少,且几乎不着色;模型组海马组织iNOS阳性染色细胞数量多,着色深;旋覆花素给药组大鼠iNOS阳性染色细胞数量较模型组减少,着色较浅,但仍比对照组数量多,着色深。Western blot显示,对照组海马组织iNOS表达量低,模型组海马组织表达量显著增高,给予旋覆花素治疗后,大鼠脑海马组织iNOS表达量明显下降。以上结果提示旋覆花素可以抑制Aβ诱导的AD模型大鼠脑海马组织iNOS基因的表达。
1.3海马组织形态学改变
形态学分析可见,正常大鼠海马神经元数目多,呈多层,排列整齐紧密。核呈圆形,大而清晰,核仁明显。神经纤维密集,排列整齐。模型组呈现典型的AD病变,可见海马神经元细胞数目明显减少,脱失现象明显,层次少而不清,排列紊乱。核固缩为三角形或多角形,浓染。神经纤维稀疏,排列紊乱,间隙扩大,神经元周围有大量小胶质细胞浸润,表明本研究建立的模型是成功的。而旋覆花素给药组大鼠上述神经元损伤明显减轻,海马神经细胞数目明显增加,排列较整齐,核固缩现象明显改善,核仁较明显。神经纤维数目也明显增加,排列较整齐。
1.4旋覆花素对大鼠学习记忆行为的影响
采用Morris水迷宫进行测试,结果显示,随着训练时段的增加,所有动物寻找站台的潜伏期越来越短,表明三组大鼠通过学习,均可对水下的站台产生空间定位记忆。训练第1天,模型组大鼠和旋覆花素给药组大鼠差别不具有统计学意义(P>0.05),对照组大鼠与模型组大鼠、旋覆花素给药组大鼠比较平均潜伏期延长,差别有统计学意义(P<0.05),说明模型组大鼠和旋覆花素给药组大鼠确有空间学习记忆能力的障碍;训练第2、3、4天,模型组大鼠平均潜伏期明显延长,与对照组大鼠、旋覆花素给药组大鼠比较差别具有统计学意义(P<0.05),而旋覆花素给药组大鼠与对照组大鼠比较,两者之间的差异不具有统计学意义(P>0.05),提示旋覆花素可以改善Aβ诱导的AD模型大鼠的空间学习记忆障碍;训练第5天,三组大鼠达稳定水平,差别均无统计学意义(P>0.05)。在空间搜索中实验中模型组大鼠最后一次跨平台次数(7.6±1.78),较对照组大鼠(12.4±2.73)及旋覆花素给药组大鼠(9.8±2.23)减少,差异具有统计学意义(P<0.05)。以上数据提示本实验造模是成功的,旋覆花素可有效改善AD模型大鼠行为学指标。
2旋覆花素对AD模型大鼠脑海马组织NF-κB、PPARγ基因表达的影响
NF-κB是一种多向性转录因子,它的结合序列存在于多种促炎和促增殖基因的调控区中,通过激活靶基因表达,在免疫、炎症、细胞周期调控、细胞增殖分化与凋亡等方面发挥重要的作用。过氧化物酶体增殖物激活受体(peroxisome proliferator activatived receptor,PPARs)是由配体激活的转录因子,属于核激素受体超家族。PPARs的活性降低与炎症介质的水平上升密切相关。近来研究认为PPARs在中枢神经系统疾病有重要作用,尤其PPARγ在脑内的表达与炎症和神经退行性变紧密联系。为了进一步探讨旋覆花素抑制AD模型大鼠海马炎症反应、改善记忆功能的机制,在本部分实验中,采用免疫组织化学及Western blot方法进一步研究旋覆花素对NF-κB、PPARγ激活的影响,以揭示旋覆花素抑制iNOS、COX-2表达的分子机制,为探明旋覆花素抑制AD脑炎症反应提供实验依据。其结果如下:
2.1旋覆花素对AD模型大鼠脑海马组织NF-κB基因表达的影响NF-κB是炎症反应的关键性转录调控因子。为了探讨NF-κB在旋覆花素抑制Aβ诱导的AD模型大鼠脑海马炎症中的作用,本实验检测了NF-κB在大鼠脑海马组织中的表达。结果发现,对照组海马组织p50阳性染色细胞数量少,着色浅;模型组海马可见大量p50阳性染色细胞,染色细胞数量多,着色深;旋覆花素给药组海马组织p50阳性染色细胞数量较模型组显著减少,着色浅。Western blot分析显示,在对照组细胞中p50主要分布于细胞浆中,细胞核中仅有少量的p50存在;Aβ诱导的AD模型大鼠脑海马组织细胞核内p50水平明显升高;服用旋覆花素的给药组大鼠脑海马组织细胞核中p50的表达量与模型组相比显著减少。三组海马组织细胞浆中p50的含量无明显差异。从上述实验结果可以看出,旋覆花素具有抑制Aβ诱导的AD模型大鼠脑海马组织p50表达与核转位的效应。
2.2旋覆花素对AD模型大鼠脑海马组织PPARγ基因表达的影响PPARγ可抑制NF-κB基因的表达,与脑内炎症反应及Aβ沉积密切相关。为了探讨旋覆花素对AD模型大鼠脑海马组织PPARγ表达的影响,我们检测了PPARγ在海马内的表达。Western blot显示,对照组海马组织表达量高,模型组海马组织表达量显著降低,给予旋覆花素治疗后,大鼠脑海马组织PPARγ表达量明显上调。提示旋覆花素具有促进Aβ诱导的AD模型大鼠脑海马组织的PPARγ表达的作用。
3旋覆花素对AD模型大鼠脑海马神经细胞凋亡的影响
细胞凋亡是贯穿于机体生命过程始终,普遍存在的一种由基因活动指导下的细胞主动性死亡现象。神经细胞凋亡是AD等退行性疾病发展过程中的重要事件,凋亡的神经细胞是不可逆的,但处于凋亡过程中的神经细胞存在不同程度的可逆性。本部分实验观察了旋覆花素对Aβ海马内注射诱导AD模型大鼠脑海马组织凋亡相关基因变化的影响,以期从凋亡角度阐明旋覆花素对AD的防治作用及其机制。
3.1旋覆花素对AD模型大鼠脑海马组织Bcl-2基因表达的影响
Bcl-2基因家族是细胞凋亡的重要调控基因,为了探讨Bcl-2在旋覆花素抑制Aβ诱导的AD模型大鼠脑海马神经细胞凋亡中的作用,本实验检测了Bcl-2在大鼠脑海马组织中的表达。免疫组化染色发现,与对照组海马组织相比,模型组和旋覆花素给药组大鼠脑海马组织的染色无明显加深,染色细胞数量无明显增多。Western blot显示,对照组大鼠脑海马组织Bcl-2表达量与模型组及旋覆花素给药组大鼠脑海马组织表达量无明显差别。以上结果提示旋覆花素对Aβ诱导的AD模型大鼠脑海马组织Bcl-2基因的表达影响不大。
3.2旋覆花素对AD模型大鼠脑海马组织Bax基因表达的影响Bax拮抗Bcl-2而发挥促凋亡作用,为了探讨旋覆花素对Aβ诱导的AD模型大鼠脑海马组织Bax基因表达的影响,我们检测了Bax在海马组织内的表达。免疫组化染色结果显示,在模型组大鼠脑海马组织中Bax表达显著增强,染色细胞数量多,着色深。应用旋覆花素治疗后,染色细胞数量减少,着色变浅。Western blot结果显示,模型组大鼠脑海马组织Bax表达较对照组显著增高,给予旋覆花素治疗后,给药组大鼠脑海马组织Bax表达下降。说明旋覆花素能抑制Aβ诱导的AD模型大鼠脑海马组织Bax基因的表达。
3.3旋覆花素对AD模型大鼠脑海马组织casepase-3基因表达的影响不管是线粒体通路、死亡受体通路,还是内质网通路,最终都是激活casepase-3导致细胞的死亡,casepase-3是凋亡的执行者,因此本实验检测了casepase-3在大鼠脑海马组织中的表达。免疫组化染色结果显示,模型组大鼠脑海马组织中casepase-3表达较对照组明显增强,染色细胞数量多,着色深。旋覆花素给药组大鼠casepase-3的表达较模型组显著减弱,染色细胞数量少,着色变浅。Western blot结果显示,模型组大鼠脑海马组织casepase-3表达较对照组大鼠显著增强,旋覆花素给药组大鼠脑海马组织casepase-3表达较模型组明显减弱。说明旋覆花素能抑制Aβ诱导的AD模型大鼠脑海马组织的casepase-3基因的表达。
3.4流式细胞术检测海马神经细胞凋亡百分率
流式细胞术检测结果显示,模型组大鼠海马神经细胞凋亡百分率(4.69±0.54 %)与对照组(3.55±0.22 %)相比增高,而旋覆花素给药组大鼠海马神经细胞凋亡百分率(3.62±0.41 %)较模型组降低,差异具有统计学意义(P<0.05)。这表明旋覆花素能够减弱Aβ25~35诱导细胞凋亡的作用。
结论
1旋覆花素显著抑制Aβ诱导的AD模型大鼠脑海马组织炎症基因iNOS、COX-2表达,抑制海马炎症反应。
2旋覆花素通过抗炎作用而改善Aβ诱导的AD模型大鼠的空间学习记忆障碍。
3旋覆花素显著抑制AD模型大鼠脑海马组织的NF-κB基因表达,而增强PPARγ基因表达,从而抑制炎症基因的表达。
4旋覆花素主要通过抑制促凋亡基因Bax以及Caspase-3的表达,抑制Aβ诱导的AD模型大鼠脑海马的神经细胞凋亡,发挥神经细胞的保护作用,而对凋亡抑制基因Bcl-2表达影响不大。
Alzheimer’s disease (AD) is an ageing-related neurodegenerative disorder with new cases every year (20-30 million individuals) worldwide. AD starts with mild memory deficits, gradually progresses to cognitive and behavioral spheres due to the extensive neuronal and synaptic loss, the intraneuronal formation of neurofibrillary tangles and the extracellar deposition of amyloid-β(Aβ) plaques in susceptible regions of the brain. Chronic inflammatory response to antigens such as Aβand NFT seem to have a role in AD process. Pro-inflammatory mediators induced by microglia and astroglia activation contributes to neuronal dysfunction and cell death, which draw patients to cognitive and behavioral dysfunction and dementia. These imply that inflammatory process inhibition may intervene AD development.
The inulicin [containing three specific sesquiterpene lactones, britannilactone (BL), 1-O-acetylbritannilactone (1-O-ABL), and 1,6-O,O-diacetylbritannilactone (1,6-O2-ABL)], isolated from inula britannica-L, is used in inflammation diseases treatment by the traditional Chinese herbal medicine. In this study, we treat AD model rats with inulicin to compare its effect on inflammatory cytokines expression so as to AD progress.
RESULTS
1 Inulicin inhibiting COX-2 and iNOS expression in AD rats ippocampus Sprague-Dawley (SD) rats weighing of 364.5±15.0 g were microinjected with Aβ25-35 into the hippocampus to induce AD model rats.
In inulicin treatment group, the animal were pretreated with inulicin (contain ABL 2.66mg /ml) dissolved in tween-80 3 days before operation, then inulicin was administered to rats at dose of ABL 26mg/kg/d by gastric gavage orally for 18 days (n=4). An equal volume of tween-80 (3 ml/rat/d) was administrated orally to model group rats (n=4). The control group animals were treated by the same operation as the other two groups but with microinjection of NS (n=4). At 21 days after surgery, the rats were killed by blood-bleeding, and the hippocampus were quickly isolated for histological and Western blot analysis.
1.1 Effect of inulicin on COX-2 expression
We studied COX-2 Expression in AD rats and matched controls. COX-2 expression were more intensive in hippocampus cell of model rats than that of control rats. Western blot analysis showed the same results as Imunohistochemistry staining. Our data demonstrated that Inulicin can inhibit COX-2 expression.
1.2 Effect of inulicin on iNOS expression
NO is a gaseous free radical, which is generated by enzymes of the nitric oxide synthase family. Excessive NO induce the cell death. In order to evaluate the anti-inflammatory activity of inulicin, we examined the iNOS expression in AD rats and matched controls. iNOS expression were more intensive in hippocampus cell of model rats than that of control rats. Western blot analysis showed the same results as Imunohistochemistry staining. Our data demonstrated that Inulicin can inhibit iNOS expression.
1.3 Innulicin effect on histomorphology of AD rats hippocampus.
Hippocampus sections of the three groups were compared by H&E-staining . There were a large of neurons in control group rats, disposed in regularity multiplayer. The nuclei were large, round and clear, so do the nucleoli. The neurofibra were close-up in regularity. Typical AD pathological changes were found in model rats. There were less neurons in indiscriminate disposition. The nuclei were pycnotic and hyperchromic, and displayed in polygonal or triangle. The neurofibra werere sparse. Microglia were recruited around neurons. These indicate that the model were successfully duplicated. Aforesaid pathological changes were ameliorated in inulicin-treated rats hippocampus.
1.4 Effect of inulicin on learning and memory
To assay behavioral defects, the three group rats were measured for escape distance. After training (day 5), all rats on day 6 were given three trials where they swam in the pool for 60 s with the platform removed. The results were significantly different for model rats vs. innulicin-treated rats, and so that were control rats in the day 2, 3 and 4(P<0.05).But there was no difference between innulicin-treated rats and control rats in the day 2, 3 and 4(P>0.05).
Also there was a significant difference between model rats and innulicin-treated rats on the crossing of former platform location(P<0.05). Taken together, all these data indicated that innulicin administration attenuated dysfunction of learning and memory in AD rats.
2 Effect of inulicin on the expression of NF-κB and PPARγin AD rats hippocampus
2.1 Effect of inulicin on NF-κB activation and translocation NF-κB is a transcriptional factors control many inflammatory cytokines expression including COX-2 and iNOS. Therefore we investigated whether inulicin control COX-2 and iNOS expression through NF-κB pathway. The cytosolic and nuclear NF-κB p50 subunit expressional levels in rats hippocampus were detected by immunochemistry and Western blot. Aβinjection into hippocampus increased p50 translocation to the nuclei, and inulicin attenuated this response. The positive cells for NF-κB were positively stained in model rat hippocampus cell but not in that of control rat. Western blot analysis showed the same results as immunochemistry staining. Our data demonstrated that inulicin can strongly inhibit NF-κB activiton.
2.2 Effect of inulicin on PPARγexpression
PPARγis related to inflammation and Aβdeposition in AD brain. We therefore examined the PPARγexpression in hippocampus after Aβinjection. The PPARγexpressional levels in rats hippocampus were detected by Western blot. Aβinjection into hippocampus decreased PPARγexpression, and inulicin attenuated this response. These data demonstrated that innulicin strongly increased PPARγexpression.
3 Inulicin inhibiting cell apoptosis of AD hippocampus
3.1 Effect of inulicin on Bcl-2/Bax expression
Bcl-2 is the prototypical antiapoptotic member of a large family of proteins involved in the modulation of cell death. Bax facilitates apoptosis by anti-Bcl-2. To assess the mechanism of inulicin inhibiting apoptosis of hippocampus neurons, Bcl-2 and Bax expressional levels were detected by Western blot and Iimmunohistochemical assays. Aβinjection into hippocampus increased Bax expression, and inulicin attenuated this response.
The expression of Bcl-2 expression was no difference among the three group rats. These data demonstrated that innulicin could inhibit apoptosis through Bax down-regulation.
3.2 Effect of inulicin on casepase-3 expression
Casepase-3 is the executor of apoptosis process and activated casepase-3 induces the cell death regardless of any apoptosis channels. Therefore we studied Casepase-3 expression in AD rats and matched controls. Casepase-3 expression were more intensive in hippocampus cell of model rats than that of control rats. The positive cells for casepase-3 were positively stained in model rat hippocampus cell but not in that of control rat. Western blot analysis showed the same results as Imunohistochemistry staining. Our data demonstrated that Inulicin can inhibit Casepase-3 expression.
3.3 Apoptosis ratio detection of hippocampus neurons by flow cytometry
Apoptosis ratio of hippocampus neurons were detected by flow cytometry. The ratio were 3.55±0.22, 3.62±0.41 and 4.69±0.54 respectively. The results were different for model rats vs. innulicin-treated rats (P < 0.05). Our data indicated that innulicin inhibited the apoptosis by Aβinjection into hippocampus.
Conclusions
1 Inulicin inhibits inflammation in hippocampus by reducing the expression of iNOS and COX-2 in AD rats.
2 Innulicin administration could attenuate learning and memory dsyfuction in AD rats by its anti-inflammatory effect.
3 Innulicin inhibits the expression of pro-inflammatory gene by down-regula- ting NF-κB expression and up-regulating PPARγexpression.
4 Iinulicin could inhibit the apoptosis by Aβinjection into hippocampus by down-regulating Bax and casepase-3 expression, but not up-regulating Bcl-2 expression.
单味中药的某一类化学成分药理作用明确,疗效稳定,毒副作用小,符合当前的医疗市场要求,对防治老年痴呆有着良好的市场前景。欧亚旋覆花(Inula Britannica)是一种传统的中草药,其化学成分有40多种,旋覆花内酯(1-o-acetylbritannilactone, ABL)是从欧亚旋覆花的氯仿提取物中分离出的有效单体成分,体外证实旋覆花内酯通过抑制NF-κB的激活而消除LPS诱导的炎症相关基因如环加氧酶(cyclo-oxygenase-2,COX-2)和诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)等的表达而发挥抑制巨噬细胞活化和抗炎作用。基于AD是一种慢性炎症性疾病,旋覆花素是旋覆花单体有效成分的特定组合,本研究通过观察旋覆花素对Aβ诱导的AD模型大鼠的干预效应,探讨其作用机制,旨在确定该有效部位的药用价值和作用途径。
1旋覆花素对AD模型大鼠脑海马组织COX-2,iNOS基因表达的影响
脑内慢性炎症反应是AD的重要病理特征,多种炎症因子能促进COX-2和iNOS的表达,COX-2和iNOS及其催化产物又可促进炎症的进一步发展,直接或间接引起神经元的死亡。本实验采用免疫组织化学及Western blot方法,分别观察旋覆花素对AD模型大鼠脑海马组织炎性基因COX-2,iNOS表达的影响。实验结果如下:
1.1旋覆花素对AD模型大鼠脑海马组织COX-2基因表达的影响作为炎症相关基因,COX-2广泛参与机体的炎症反应,本实验观察了旋覆花素对COX-2表达的影响。对照组海马组织COX-2阳性染色细胞数量少,且几乎不着色;模型组海马组织COX-2阳性染色细胞数量多,着色深;旋覆花素给药组大鼠COX-2阳性染色细胞数量较模型组减少,着色较浅,但仍比对照组数量多,着色深。Western blot显示,对照组海马组织COX-2表达量低,模型组海马组织表达量显著增高,给予旋覆花素治疗后,大鼠脑海马组织COX-2表达量明显下降。以上结果提示旋覆花素可以抑制Aβ诱导的AD模型大鼠脑海马组织的COX-2基因的表达。
1.2旋覆花素对AD模型大鼠脑海马组织iNOS基因表达的影响激活的小胶质细胞活化iNOS产生大量具有神经毒性的NO,导致神经元死亡。本实验观察了旋覆花素对iNOS表达的影响。对照组海马组织iNOS阳性染色细胞数量少,且几乎不着色;模型组海马组织iNOS阳性染色细胞数量多,着色深;旋覆花素给药组大鼠iNOS阳性染色细胞数量较模型组减少,着色较浅,但仍比对照组数量多,着色深。Western blot显示,对照组海马组织iNOS表达量低,模型组海马组织表达量显著增高,给予旋覆花素治疗后,大鼠脑海马组织iNOS表达量明显下降。以上结果提示旋覆花素可以抑制Aβ诱导的AD模型大鼠脑海马组织iNOS基因的表达。
1.3海马组织形态学改变
形态学分析可见,正常大鼠海马神经元数目多,呈多层,排列整齐紧密。核呈圆形,大而清晰,核仁明显。神经纤维密集,排列整齐。模型组呈现典型的AD病变,可见海马神经元细胞数目明显减少,脱失现象明显,层次少而不清,排列紊乱。核固缩为三角形或多角形,浓染。神经纤维稀疏,排列紊乱,间隙扩大,神经元周围有大量小胶质细胞浸润,表明本研究建立的模型是成功的。而旋覆花素给药组大鼠上述神经元损伤明显减轻,海马神经细胞数目明显增加,排列较整齐,核固缩现象明显改善,核仁较明显。神经纤维数目也明显增加,排列较整齐。
1.4旋覆花素对大鼠学习记忆行为的影响
采用Morris水迷宫进行测试,结果显示,随着训练时段的增加,所有动物寻找站台的潜伏期越来越短,表明三组大鼠通过学习,均可对水下的站台产生空间定位记忆。训练第1天,模型组大鼠和旋覆花素给药组大鼠差别不具有统计学意义(P>0.05),对照组大鼠与模型组大鼠、旋覆花素给药组大鼠比较平均潜伏期延长,差别有统计学意义(P<0.05),说明模型组大鼠和旋覆花素给药组大鼠确有空间学习记忆能力的障碍;训练第2、3、4天,模型组大鼠平均潜伏期明显延长,与对照组大鼠、旋覆花素给药组大鼠比较差别具有统计学意义(P<0.05),而旋覆花素给药组大鼠与对照组大鼠比较,两者之间的差异不具有统计学意义(P>0.05),提示旋覆花素可以改善Aβ诱导的AD模型大鼠的空间学习记忆障碍;训练第5天,三组大鼠达稳定水平,差别均无统计学意义(P>0.05)。在空间搜索中实验中模型组大鼠最后一次跨平台次数(7.6±1.78),较对照组大鼠(12.4±2.73)及旋覆花素给药组大鼠(9.8±2.23)减少,差异具有统计学意义(P<0.05)。以上数据提示本实验造模是成功的,旋覆花素可有效改善AD模型大鼠行为学指标。
2旋覆花素对AD模型大鼠脑海马组织NF-κB、PPARγ基因表达的影响
NF-κB是一种多向性转录因子,它的结合序列存在于多种促炎和促增殖基因的调控区中,通过激活靶基因表达,在免疫、炎症、细胞周期调控、细胞增殖分化与凋亡等方面发挥重要的作用。过氧化物酶体增殖物激活受体(peroxisome proliferator activatived receptor,PPARs)是由配体激活的转录因子,属于核激素受体超家族。PPARs的活性降低与炎症介质的水平上升密切相关。近来研究认为PPARs在中枢神经系统疾病有重要作用,尤其PPARγ在脑内的表达与炎症和神经退行性变紧密联系。为了进一步探讨旋覆花素抑制AD模型大鼠海马炎症反应、改善记忆功能的机制,在本部分实验中,采用免疫组织化学及Western blot方法进一步研究旋覆花素对NF-κB、PPARγ激活的影响,以揭示旋覆花素抑制iNOS、COX-2表达的分子机制,为探明旋覆花素抑制AD脑炎症反应提供实验依据。其结果如下:
2.1旋覆花素对AD模型大鼠脑海马组织NF-κB基因表达的影响NF-κB是炎症反应的关键性转录调控因子。为了探讨NF-κB在旋覆花素抑制Aβ诱导的AD模型大鼠脑海马炎症中的作用,本实验检测了NF-κB在大鼠脑海马组织中的表达。结果发现,对照组海马组织p50阳性染色细胞数量少,着色浅;模型组海马可见大量p50阳性染色细胞,染色细胞数量多,着色深;旋覆花素给药组海马组织p50阳性染色细胞数量较模型组显著减少,着色浅。Western blot分析显示,在对照组细胞中p50主要分布于细胞浆中,细胞核中仅有少量的p50存在;Aβ诱导的AD模型大鼠脑海马组织细胞核内p50水平明显升高;服用旋覆花素的给药组大鼠脑海马组织细胞核中p50的表达量与模型组相比显著减少。三组海马组织细胞浆中p50的含量无明显差异。从上述实验结果可以看出,旋覆花素具有抑制Aβ诱导的AD模型大鼠脑海马组织p50表达与核转位的效应。
2.2旋覆花素对AD模型大鼠脑海马组织PPARγ基因表达的影响PPARγ可抑制NF-κB基因的表达,与脑内炎症反应及Aβ沉积密切相关。为了探讨旋覆花素对AD模型大鼠脑海马组织PPARγ表达的影响,我们检测了PPARγ在海马内的表达。Western blot显示,对照组海马组织表达量高,模型组海马组织表达量显著降低,给予旋覆花素治疗后,大鼠脑海马组织PPARγ表达量明显上调。提示旋覆花素具有促进Aβ诱导的AD模型大鼠脑海马组织的PPARγ表达的作用。
3旋覆花素对AD模型大鼠脑海马神经细胞凋亡的影响
细胞凋亡是贯穿于机体生命过程始终,普遍存在的一种由基因活动指导下的细胞主动性死亡现象。神经细胞凋亡是AD等退行性疾病发展过程中的重要事件,凋亡的神经细胞是不可逆的,但处于凋亡过程中的神经细胞存在不同程度的可逆性。本部分实验观察了旋覆花素对Aβ海马内注射诱导AD模型大鼠脑海马组织凋亡相关基因变化的影响,以期从凋亡角度阐明旋覆花素对AD的防治作用及其机制。
3.1旋覆花素对AD模型大鼠脑海马组织Bcl-2基因表达的影响
Bcl-2基因家族是细胞凋亡的重要调控基因,为了探讨Bcl-2在旋覆花素抑制Aβ诱导的AD模型大鼠脑海马神经细胞凋亡中的作用,本实验检测了Bcl-2在大鼠脑海马组织中的表达。免疫组化染色发现,与对照组海马组织相比,模型组和旋覆花素给药组大鼠脑海马组织的染色无明显加深,染色细胞数量无明显增多。Western blot显示,对照组大鼠脑海马组织Bcl-2表达量与模型组及旋覆花素给药组大鼠脑海马组织表达量无明显差别。以上结果提示旋覆花素对Aβ诱导的AD模型大鼠脑海马组织Bcl-2基因的表达影响不大。
3.2旋覆花素对AD模型大鼠脑海马组织Bax基因表达的影响Bax拮抗Bcl-2而发挥促凋亡作用,为了探讨旋覆花素对Aβ诱导的AD模型大鼠脑海马组织Bax基因表达的影响,我们检测了Bax在海马组织内的表达。免疫组化染色结果显示,在模型组大鼠脑海马组织中Bax表达显著增强,染色细胞数量多,着色深。应用旋覆花素治疗后,染色细胞数量减少,着色变浅。Western blot结果显示,模型组大鼠脑海马组织Bax表达较对照组显著增高,给予旋覆花素治疗后,给药组大鼠脑海马组织Bax表达下降。说明旋覆花素能抑制Aβ诱导的AD模型大鼠脑海马组织Bax基因的表达。
3.3旋覆花素对AD模型大鼠脑海马组织casepase-3基因表达的影响不管是线粒体通路、死亡受体通路,还是内质网通路,最终都是激活casepase-3导致细胞的死亡,casepase-3是凋亡的执行者,因此本实验检测了casepase-3在大鼠脑海马组织中的表达。免疫组化染色结果显示,模型组大鼠脑海马组织中casepase-3表达较对照组明显增强,染色细胞数量多,着色深。旋覆花素给药组大鼠casepase-3的表达较模型组显著减弱,染色细胞数量少,着色变浅。Western blot结果显示,模型组大鼠脑海马组织casepase-3表达较对照组大鼠显著增强,旋覆花素给药组大鼠脑海马组织casepase-3表达较模型组明显减弱。说明旋覆花素能抑制Aβ诱导的AD模型大鼠脑海马组织的casepase-3基因的表达。
3.4流式细胞术检测海马神经细胞凋亡百分率
流式细胞术检测结果显示,模型组大鼠海马神经细胞凋亡百分率(4.69±0.54 %)与对照组(3.55±0.22 %)相比增高,而旋覆花素给药组大鼠海马神经细胞凋亡百分率(3.62±0.41 %)较模型组降低,差异具有统计学意义(P<0.05)。这表明旋覆花素能够减弱Aβ25~35诱导细胞凋亡的作用。
结论
1旋覆花素显著抑制Aβ诱导的AD模型大鼠脑海马组织炎症基因iNOS、COX-2表达,抑制海马炎症反应。
2旋覆花素通过抗炎作用而改善Aβ诱导的AD模型大鼠的空间学习记忆障碍。
3旋覆花素显著抑制AD模型大鼠脑海马组织的NF-κB基因表达,而增强PPARγ基因表达,从而抑制炎症基因的表达。
4旋覆花素主要通过抑制促凋亡基因Bax以及Caspase-3的表达,抑制Aβ诱导的AD模型大鼠脑海马的神经细胞凋亡,发挥神经细胞的保护作用,而对凋亡抑制基因Bcl-2表达影响不大。
Alzheimer’s disease (AD) is an ageing-related neurodegenerative disorder with new cases every year (20-30 million individuals) worldwide. AD starts with mild memory deficits, gradually progresses to cognitive and behavioral spheres due to the extensive neuronal and synaptic loss, the intraneuronal formation of neurofibrillary tangles and the extracellar deposition of amyloid-β(Aβ) plaques in susceptible regions of the brain. Chronic inflammatory response to antigens such as Aβand NFT seem to have a role in AD process. Pro-inflammatory mediators induced by microglia and astroglia activation contributes to neuronal dysfunction and cell death, which draw patients to cognitive and behavioral dysfunction and dementia. These imply that inflammatory process inhibition may intervene AD development.
The inulicin [containing three specific sesquiterpene lactones, britannilactone (BL), 1-O-acetylbritannilactone (1-O-ABL), and 1,6-O,O-diacetylbritannilactone (1,6-O2-ABL)], isolated from inula britannica-L, is used in inflammation diseases treatment by the traditional Chinese herbal medicine. In this study, we treat AD model rats with inulicin to compare its effect on inflammatory cytokines expression so as to AD progress.
RESULTS
1 Inulicin inhibiting COX-2 and iNOS expression in AD rats ippocampus Sprague-Dawley (SD) rats weighing of 364.5±15.0 g were microinjected with Aβ25-35 into the hippocampus to induce AD model rats.
In inulicin treatment group, the animal were pretreated with inulicin (contain ABL 2.66mg /ml) dissolved in tween-80 3 days before operation, then inulicin was administered to rats at dose of ABL 26mg/kg/d by gastric gavage orally for 18 days (n=4). An equal volume of tween-80 (3 ml/rat/d) was administrated orally to model group rats (n=4). The control group animals were treated by the same operation as the other two groups but with microinjection of NS (n=4). At 21 days after surgery, the rats were killed by blood-bleeding, and the hippocampus were quickly isolated for histological and Western blot analysis.
1.1 Effect of inulicin on COX-2 expression
We studied COX-2 Expression in AD rats and matched controls. COX-2 expression were more intensive in hippocampus cell of model rats than that of control rats. Western blot analysis showed the same results as Imunohistochemistry staining. Our data demonstrated that Inulicin can inhibit COX-2 expression.
1.2 Effect of inulicin on iNOS expression
NO is a gaseous free radical, which is generated by enzymes of the nitric oxide synthase family. Excessive NO induce the cell death. In order to evaluate the anti-inflammatory activity of inulicin, we examined the iNOS expression in AD rats and matched controls. iNOS expression were more intensive in hippocampus cell of model rats than that of control rats. Western blot analysis showed the same results as Imunohistochemistry staining. Our data demonstrated that Inulicin can inhibit iNOS expression.
1.3 Innulicin effect on histomorphology of AD rats hippocampus.
Hippocampus sections of the three groups were compared by H&E-staining . There were a large of neurons in control group rats, disposed in regularity multiplayer. The nuclei were large, round and clear, so do the nucleoli. The neurofibra were close-up in regularity. Typical AD pathological changes were found in model rats. There were less neurons in indiscriminate disposition. The nuclei were pycnotic and hyperchromic, and displayed in polygonal or triangle. The neurofibra werere sparse. Microglia were recruited around neurons. These indicate that the model were successfully duplicated. Aforesaid pathological changes were ameliorated in inulicin-treated rats hippocampus.
1.4 Effect of inulicin on learning and memory
To assay behavioral defects, the three group rats were measured for escape distance. After training (day 5), all rats on day 6 were given three trials where they swam in the pool for 60 s with the platform removed. The results were significantly different for model rats vs. innulicin-treated rats, and so that were control rats in the day 2, 3 and 4(P<0.05).But there was no difference between innulicin-treated rats and control rats in the day 2, 3 and 4(P>0.05).
Also there was a significant difference between model rats and innulicin-treated rats on the crossing of former platform location(P<0.05). Taken together, all these data indicated that innulicin administration attenuated dysfunction of learning and memory in AD rats.
2 Effect of inulicin on the expression of NF-κB and PPARγin AD rats hippocampus
2.1 Effect of inulicin on NF-κB activation and translocation NF-κB is a transcriptional factors control many inflammatory cytokines expression including COX-2 and iNOS. Therefore we investigated whether inulicin control COX-2 and iNOS expression through NF-κB pathway. The cytosolic and nuclear NF-κB p50 subunit expressional levels in rats hippocampus were detected by immunochemistry and Western blot. Aβinjection into hippocampus increased p50 translocation to the nuclei, and inulicin attenuated this response. The positive cells for NF-κB were positively stained in model rat hippocampus cell but not in that of control rat. Western blot analysis showed the same results as immunochemistry staining. Our data demonstrated that inulicin can strongly inhibit NF-κB activiton.
2.2 Effect of inulicin on PPARγexpression
PPARγis related to inflammation and Aβdeposition in AD brain. We therefore examined the PPARγexpression in hippocampus after Aβinjection. The PPARγexpressional levels in rats hippocampus were detected by Western blot. Aβinjection into hippocampus decreased PPARγexpression, and inulicin attenuated this response. These data demonstrated that innulicin strongly increased PPARγexpression.
3 Inulicin inhibiting cell apoptosis of AD hippocampus
3.1 Effect of inulicin on Bcl-2/Bax expression
Bcl-2 is the prototypical antiapoptotic member of a large family of proteins involved in the modulation of cell death. Bax facilitates apoptosis by anti-Bcl-2. To assess the mechanism of inulicin inhibiting apoptosis of hippocampus neurons, Bcl-2 and Bax expressional levels were detected by Western blot and Iimmunohistochemical assays. Aβinjection into hippocampus increased Bax expression, and inulicin attenuated this response.
The expression of Bcl-2 expression was no difference among the three group rats. These data demonstrated that innulicin could inhibit apoptosis through Bax down-regulation.
3.2 Effect of inulicin on casepase-3 expression
Casepase-3 is the executor of apoptosis process and activated casepase-3 induces the cell death regardless of any apoptosis channels. Therefore we studied Casepase-3 expression in AD rats and matched controls. Casepase-3 expression were more intensive in hippocampus cell of model rats than that of control rats. The positive cells for casepase-3 were positively stained in model rat hippocampus cell but not in that of control rat. Western blot analysis showed the same results as Imunohistochemistry staining. Our data demonstrated that Inulicin can inhibit Casepase-3 expression.
3.3 Apoptosis ratio detection of hippocampus neurons by flow cytometry
Apoptosis ratio of hippocampus neurons were detected by flow cytometry. The ratio were 3.55±0.22, 3.62±0.41 and 4.69±0.54 respectively. The results were different for model rats vs. innulicin-treated rats (P < 0.05). Our data indicated that innulicin inhibited the apoptosis by Aβinjection into hippocampus.
Conclusions
1 Inulicin inhibits inflammation in hippocampus by reducing the expression of iNOS and COX-2 in AD rats.
2 Innulicin administration could attenuate learning and memory dsyfuction in AD rats by its anti-inflammatory effect.
3 Innulicin inhibits the expression of pro-inflammatory gene by down-regula- ting NF-κB expression and up-regulating PPARγexpression.
4 Iinulicin could inhibit the apoptosis by Aβinjection into hippocampus by down-regulating Bax and casepase-3 expression, but not up-regulating Bcl-2 expression.
引文
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15 Dae Y, Hwang, Kab R, et al. Alterations in behavior, amyloid β-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer’s disease. FASEB J, 2002, 12(7):805~813
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21 Smith DP, Ciccotosto GD, Tew DJ, et al. Concentration dependent Cu2+ induced aggregation and dityrosine formation of the Alzheimer's disease amyloid-beta peptide. Biochemistry, 2007, 46(10):2881~2891
22 Combs OK, Kzrlo JC, Kao SC, et al. beta-Amyliod stimulation do microglia and nonocytes results in TNF alpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosic, 2001, 21(4):1179~1188
23 Weldon DT, Rogers SD, Ghilardi JR, et al. Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide sythase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci, 1998, 18(6):2161~2173
24 Ishii K, Muelhauser F, Leibl U, et al. Subacute NO generation induced by Alzheimer’s beta-amyloid in the living brain: reversal by inhibition of inducible NO synthase. FASEB J, 2000, 14(11):1485~1489
25 Simic G, Lucassen PJ, Krsnik Z, et al. nNOS expession in reactive astrocytes correlates with increased cell death related DNA damage in the hippocampus and entorhinal cortex in Alzheimer’s. Exp Neurol, 2000,165(1):12~16
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2 Sastre M, Dewachter I, Rossner S, et al. Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPAR gamma. Proc Natl Acad Sci USA, 2006,103(2): 443~448
3 McGeer PL, Rogers J, McGeer EG. Inflammation, anti-inflammatory agents and Alzheimer disease: the last 12 years. J Alzheimers Dis, 2006, 9(3 Suppl):271~276
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5 Scacchi R, Pinto A, Gambina G, et al. The peroxisome proliferator- activated receptor gamma(PPAR-gamma2) Pro12Ala polymorphism is associated with higher risk for Alzheimer's disease in octogenarians. Brain Res, 2007, 1139:1~5
6 Koivisto AM, Helisalmi S, Pihlajamaki J, et al. Association analysis of peroxisome proliferator-activated receptor gamma polymorphisms and late onset Alzheimer's disease in the Finnish population. Dement Geriatr Cogn Disord, 2006, 22(5-6):449~453
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8 Heneka MT, Feinstein DL, Galea E, et al. Peroxisome proliferator- activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase. J Neuroimmunol, 1999, 100(1-2):156~168
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