烟碱对AD大鼠认知功能障碍的作用及机制的研究
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摘要
Alzheimer's病(AD)是神经系统变性疾病,表现为学习、记忆能力下降,智能减退,生活自理能力降低。由于社会老龄化,AD成为老年人继心脏病、肿瘤和卒中之后的第四位死亡原因。AD患者智能下降,生活自理能力逐渐丧失,在治疗和护理上耗费大量的精力和费用,给家庭和社会带来沉重的经济压力。
AD的特征性病理改变是老年斑(SP)、神经原纤维缠结(NFT)、神经元颗粒空泡变性、脑血管淀粉样变性等。由于AD的确切病因和发病机制并不完全清楚,因而在临床缺乏对AD明确有效的治疗措施。近年来的研究表明,大脑局部过度的炎性反应引起大量的细胞因子释放,在AD的发生和发展中起重要作用。炎性反应同老年斑和神经原纤维缠结为AD的主要特征。针对AD的病理特点,我们认为阻断AD的炎性反应是一治疗靶点。
β-淀粉样蛋白(Aβ)可激活小胶质细胞导致炎性细胞因子IL-1β、IL-6、TNF-α等的分泌增加,小胶质细胞分泌的IL-1β又刺激星形胶质细胞活化,活化的星形胶质细胞进一步分泌炎性细胞因子,加重Aβ的沉积,从而形成“恶性循环”,导致神经元和突触的不可逆损害,出现神经病理和临床改变。
人们开始用非甾体抗炎药(NSAIDs)治疗AD。研究表明,长期应用NSAIDs可以降低AD发病的危险性并可缓解AD的症状。故抗炎治疗可以延缓AD的发生,缓解AD的临床症状。研究证实烟碱可抑制机体的炎性反应。给实验动物注射烟碱,炎性反应减轻。有学者经过流行病学研究,提出吸烟可降低AD发病的危险性。给AD患者使用烟碱透皮贴剂,认知功能得到改善。
烟碱在中枢神经系统的受体是胶质细胞、神经元表面的α7nAChR,胶质细胞是中枢神经系统内分泌炎性介质的主要细胞。我们这项研究的目的是探讨在AD大鼠内,烟碱作用于胶质细胞表面的α7nAChR对抗Aβ引起的炎性反应,研究烟碱对AD大鼠认知功能改善的作用机制。
我们给予AD模型大鼠口服烟碱,通过Morris水迷宫实验,并检测α7nAChR、IL-1β、IL-6等的变化,观察烟碱对AD大鼠认知功能的改善作用,探讨烟碱的作用机制。在海马神经组织细胞混合培养体系中加入烟碱和Aβ_(25-35),检测炎性细胞因子IL-1β、IL-6变化,探讨Aβ_(25-35)对神经元的损害作用,烟碱的抗炎效应和对神经细胞的保护作用。
主要研究内容和结果:
1.烟碱对AD大鼠海马炎性反应的作用
动物实验分三组,烟碱AD组、AD对照组、正常对照组。给予S-D大鼠口服烟碱,然后在大鼠双侧海马区注射Aβ_(25-35),建立烟碱AD大鼠模型。给S-D大鼠双侧海马区注射Aβ_(25-35),建立AD大鼠模型。
通过Morris水迷宫实验,检测烟碱AD组、AD组大鼠和正常对照组大鼠学习记忆能力的变化。烟碱AD组大鼠在平台定位航行实验中潜伏期较正常对照组有所延长,在平台象限的游泳时间百分比和游泳距离百分比较正常对照组降低,但高于AD对照组,差异明显。AD组大鼠平台定位航行实验潜伏期虽有下降趋势,但不稳定,在平台象限搜索次数较少,目的性不明确,与烟碱AD组、正常对照组相比差异明显。对三组动物进行方差分析,差异具有显著意义。
对海马组织α7nAChR蛋白含量进行检测,AD组第1天、第7天、第15天α7nAChR蛋白明显下降,与正常对照组相比,差异显著。烟碱AD组第1天、第7天、第15天下降,但下降幅度不如AD组明显,与AD组相比,存在差异;与正常组相比,无差异。
AD组海马组织IL-1β、IL-6在1-15天明显升高,第7天达峰值,第15天仍明显高于正常对照组。烟碱AD组IL-1β、IL-6升高,但与AD组相比,升高幅度不大,存在显著性差异;与正常对照组相比,存在差异。
α7nAChR免疫染色阳性细胞:α7nAChR免疫染色阳性物质位于细胞膜和细胞突起。正常对照组α7nAChR免疫阳性物质染色深,阳性细胞排列规则、密集。烟碱AD组,α7nAChR免疫阳性物质染色较深,阳性细胞排列比较有规则,接近正常对照组。AD组α7nAChR免疫染色略浅,阳性细胞排列欠规则。
IB4免疫染色阳性小胶质细胞:IB4免疫染色阳性物质位于整个细胞区域。正常对照组海马区IB4免疫染色阳性细胞数目少、染色浅,胞体扁长,分支细、短;烟碱AD组:海马区IB4阳性细胞数较正常组增多,染色浅,胞体形态与正常组类似;AD组:海马区IB4免疫染色阳性细胞数目明显增多,胞体增大,突起增长增粗,部分IB4阳性细胞呈灌木样或杆状。
GFAP免疫染色阳性星形胶质细胞:GFAP免疫染色阳性物质位于整个细胞区域。正常对照组海马区GFAP免疫染色阳性细胞数目少,染色淡而均匀,胞体小,突起细短;烟碱AD组海马区GFAP免疫染色阳性细胞数目增多,染色加深,部分细胞胞体增大,突起增长;AD组海马区GFAP免疫染色阳性细胞明显增多,胞体增大,突起增长增粗。
IL-1β免疫染色阳性细胞:IL-1β免疫染色阳性物质主要位于细胞体。正常对照组、烟碱AD组大鼠海马区IL-1β免疫染色阳性物质反应弱,染色浅。AD组海马区域IL-1β免疫染色阳性增强,阳性细胞增多。
2、烟碱抗Aβ_(25-35)神经毒性作用研究
用2d龄Sprague-Dawley大鼠海马神经组织细胞混合培养体系。实验分为:正常对照组、Aβ(2μM)组、烟碱(10μM)+Aβ(2μM)组、烟碱(20μM)+Aβ(2μM)组。
无菌分离海马组织,培养海马神经组织细胞混合体系,到第5天,在相差显微镜下观察,培养细胞生长良好,细胞扁平,神经元四周出现明显光晕,胞体增大,突起长出并逐渐伸长,部分联成网络。分别按10μM、20μM浓度加入烟碱,孵育1h后加入Aβ(2μM),再孵育24小时。检测细胞培养上清液IL-1β、IL-6含量,测定神经元胞体直径和突起长度及细胞生存率。
烟碱Aβ组细胞培养上清液中IL-1β、IL-6含量增高,烟碱浓度10uM时细胞培养上清液中IL-1β、IL-6含量与正常对照组相比差异明显,而烟碱浓度在20uM时细胞培养上清液中IL-1β、IL-6含量与正常对照组相比差异不明显。烟碱Aβ组两种浓度下,细胞培养上清液中IL-1β、IL-6含量与Aβ组相比,差异显著。
神经元荧光染色,正常对照组神经元胞体饱满,细胞轮廓圆滑,神经突起形成网络联系;烟碱Aβ组,神经元细胞形态接近正常,神经元胞体直径和突起长度与正常组相差不明显;Aβ组,神经元数目减少,部分细胞脱离底壁而漂浮,损伤神经元逐渐退化、崩解,出现沉淀,神经突起断裂,神经元胞体直径增大,胞体肿胀,突起回缩。
烟碱(10μM)+Aβ(2μM)组、烟碱(20μM)+Aβ(2μM)组细胞存活率分别为54.7%、62.27%。而Aβ组细胞存活率只有29.57%。烟碱具有抗Aβ神经毒性,提高细胞生存率,保护神经元的作用。
结论
大鼠口服烟碱后,在其双侧海马区注射Aβ_(25-35),成功建立了烟碱AD大鼠模型。
在Morris水迷宫实验中,烟碱AD组大鼠平台定位航行实验的潜伏期比正常对照组有延长,但比AD大鼠明显缩短;在空间探索实验中,烟碱AD组大鼠平台象限游泳时间百分比、游泳距离百分比较AD组大鼠明显增高。证实烟碱可改善AD大鼠认知功能。
烟碱AD组与AD组比较,海马小胶质细胞和星形胶质细胞的活性降低,IL-1β、IL-6分泌减少,α7nAChR下降不明显。在α7nAChR介导下,烟碱抑制了胶质细胞的炎性细胞因子IL-1β、IL-6分泌,烟碱有明显的抗炎效应,烟碱对神经元具有保护作用。
在海马神经组织细胞混合培养体系中证实烟碱可对抗Aβ_(25-35)的细胞毒性作用。烟碱预处理后,抑制了Aβ_(25-35)诱导胶质细胞分泌IL-1β、IL-6的作用,Aβ_(25-35)对神经元的细胞毒性作用降低,细胞生存率提高。
Alzheimer's disease(AD) is a neurodegeneration disease of the nervous system.AD patients present with impairment in learning,memory and intelligence,and loss of the self-care ability at late stages.Due to aging of the population,AD has become the fourth cause of death of the elderly next to heart disease,tumor and stroke.The treatment and nursing of AD patients are costly,bringing heavy financial burdens to the family and the society as well.
The hallmarks of AD pathology are senile plaques,neurofibrillary tangles, granulovacuolar degeneration of neurons and cerebrovascular amyloidosis.The precise etiology and pathogenesis of AD are unclear;therefore,an effective therapy of AD is not available yet.Recent studies have demonstrated that excessive,regional inflammatory reaction in the brain may cause the release of large amounts of free radicals and cytokines, resulting in the incidence and progression of AD.As with senile plaque(SP) and neurofibrillary tangles(NFTs),inflammatory reaction is also a pathologic hallmark of AD. In light of the pathologic hallmarks of AD,we consider blockage of inflammatory reaction as one of the therapeutic targets for AD.
Aβand neurofibrils may activate microglial cells,leading to enhanced expression of cell surface MHC-Ⅱand increased secretion of inflammatory cytokines such as IL-1β,IL-6 and TNFα.IL-1β,in turn,activates astrocytes,and activated astrocytes secrete more inflammatory cytokines,resulting in Aβdeposition and neurofibrillary tangles;therefore,a vicious cycle forms,which causes irreversible damages to neurons and synapses as well as pathologic and clinical changes of the nervous system.
Inflammatory cytokines resulting from brain inflammation are also trigger factors for brain neuroinflammation.Accordingly,non-steroid anti-inflammatory drugs(NSAIDs) are used to treat AD.It has been shown that the long-term use of NSAIDs may reduce the risk of AD and ameliorate the symptoms of AD patients.Therefor,anti-inflammation therapy can delay the onset of AD as well as improve cognitive function in the aymptoms of AD.
Recent studies suggest that nicotine can inhibbite the inflammation.The rats are chronically administrated with nicotine.Results showed that nicotine can decrease the chemotaxis/chemokinesis of peripheral vlood mononuclear cells,impaire T-help cells antigen present,attenuate T-cell activation.Nicotine-treatment decrease T-cell proliferation, inhibite the migration of leukocytes,attenuates the plasma effusion induced inflammation.
Smoking may also reduce the risk of AD.Treatment with nicotine transdermal patches may improve the intelligence of AD patients as revealed by the Coruner's continuous performance test(CPT).There is a cholinergic anti-inflammatory pathway in the body, through which acetylcholine or nicotine may reduce lipopolysaccharide-induced release of inflammatory cytokines such as TNF-α,IL-1βand IL-6 viaα7nAChR on macrophages and thus lessen lipopolysaccharide-induced inflammatory response.Since neurons,microglial cells and astrocytes expressα7nAChR in the central nervous system,is there a similar cholinergic anti-inflammatory pathway in the central nervous system?
Acute treatment of ex vivo microglial cells with nicotine may reduce LPS-induced secretion of TNF-α.Nevertheless,the effect of nicotine on Aβactivated microglial cells, secretion of IL-1βand IL-6 has not been reported yet.
In the study,we administered AD model rats with nicotine orally,and detected the changes in the contents ofα7nAChR,IL-1β,and IL-6,so as to observe the effect of nicotine on cognition and release of inflammatory cytokines.Nicotine and Aβwere added into the mixed nerve cell cultures,and the protective effect of nicotine on neurons was observed; meanwhile,the changes in IL-1 and IL-6 were detected,so as to further elucidate the anti-inflammatory effect of nicotine.
Main contents and results:
1.Effect of nicotine on Aβ-induced inflammatory reaction in the nervous system
S-D rats were orally administered with nicotine to perform nicotine pretreatment.Then, Aβ25-35 was injected into bilateral hippocampus to establish the nicotinic AD rat model and the AD control rat model.The differences in learning and memory among the AD nicotine rats,AD rats and normal rats were observed by the Morris water maze test.
During the place navigation test,the latency was longer in the nicotine AD group than in the normal control group,and the percentages of swimming time and swimming distance at each quadrant were lower in the nicotine AD group than in the normal control group,but were still significantly higher than in the AD control group.In the AD control group,the latency tended to decrease,but was not stable,and the frequency of search at each quadrant was low and the purposiveness was not clear,and there were significant differences in the regards between the nicotine AD group and the normal control group.Compared to the normal control group,rats of the nicotine AD group presented with certain impairment of intelligence,but the impairment was significantly milder than that in the AD group. Variance analysis revealed significant differences among the three groups of animals.
Western blot analysis ofα7nAChR protein in hippocampal tissue revealed thatα7nAChR protein content was decreased slightly in the nicotine AD group at days 1,7 and 15 after injection of Aβ(P＜0.05 at day 1),and there were no significant differences between the nicotine AD group and the normal control group.However,in the AD group,α7nAChR protein content was decreased at days 1,7 and 15 after injection of Aβand existed till day 15,and there were significant differences between the nicotine AD group and the normal control group.
α7nA ChR immunoreactive cells:In the normal control group,cells were darkly stained and well-arranged in great density.In the nicotine AD group,cells were stained relatively darkly and arranged relatively well,just similar to cells of the normal control group.However,in the AD group,cells were faintly stained and arranged in mess.
The levels of IL-1βand IL-6 in the hippocampal tissue:ELISA results indicated that IL-1βand IL-6 contents of hippocampal tissue were low in the normal control group and increased slightly in the nicotine AD group following injection of Aβ(the contents were the highest at day 1 and then decreased gradually),and there were no significant differences between the nicotine AD group and the normal control group.However,in the AD group, IL-1βand IL-6 contents increased drastically and reached a peak at day 7 and then decreased,but the contents were still significantly higher than those in the normal control group and the nicotine AD group at day 15.
IL-1βimmunoreactive cells:In the hippocampus of rats of the normal control group and the nicotine AD group,IL-1βimmunoreactivity was weak and cells were faintly stained; however,in the AD group,IL-1βimmunoreactivity was strong and cells were darkly stained.
IB4 immunoreactive microglial cells:In the normal control group:the number of IB4 immunoreactive hippocampal cells was small;cells were faintly stained,with flat and long body and short and thin processes.In the nicotine AD group:the number of IB4 immunoreactive hippocampal cells was increased compared to the normal group,and cells were faintly stained with similar morphology with cells of the normal group.In the AD group:The number of IB4 immunoreactive hippocampal cells was significantly increased, and cell body size was increased,with prolonged and thickened processes.Some of the IB4 immunoreactive cells were of shrub- or rod-shape.
GFAP immunoreactive astrocytes:In the normal control group:the number of GFAP immunoreactive hippocampal cells was small,cells were faintly and evenly stained,cell body size was small,and nerve processes were thin and short.In the nicotine AD group:the number of GFAP immunoreactive hippocampal cells was increased,cells were darkly stained,the body size of some cells was increased,and nerve processes were prolonged.In the AD group:The number of GFAP immunoreactive hippocampal cells was significantly increased,the size of cell body was increased,and nerve processes were thickened.
2.Counteraction of nicotine against Aβ_(25-35) neurotoxicity
The mixed hippocampal cells of 2d-old Sprague-Dawley rats were cultured.There were four groups:the normal control group,Aβ(2μM) group,the nicotine(10μM) +Aβ(2μM) group and the nicotine(20μM)+Aβ(2μM) group.
Hippocampal tissue was isolated under sterile condition,and mixed hippocampal nerve cells were cultured.At day 5 of culture,cells were observed under phase-contrast microscope.Cells grew well,cell body was flat,with marked halos around,body size was increased,and nerve processes were long and extended gradually,forming a network.The hippocampal cultures incubation with differentia concentration nicotine for 1h prior to treatment with Aβ_(25-3).After 24h incubation of cells with various concentrations of nicotine or nicotine +Aβ,IL-1βand IL-6 contents in culture supernatants were determined by ELISA and neurons were subjected to fluorescence staining,followed by determination of neuron body diameter and process length as well as cell viability assessment by the MTT assay.
IL-1βand IL-6 contents in culture supernatants:In the nicotine Aβgroup,IL-1βand IL-6 contents were increased mildly after addition of Aβ;the differences in IL-1βand IL-6 contents were not significant between the nicotine Aβgroup and the normal control group, but were significant between the nicotine Aβgroup and the Aβgroup,suggesting that nicotine has inhibitory effect on Aβ-induced release of IL-1βand IL-6.Provided with a constant Aβconcentration,the inhibitory effect was related to the nicotine concentration.In the Aβgroup,IL-1βand IL-6 contents in culture supernatants were significantly higher than those in the nicotine Aβgroup and the normal control group,confirming that Aβmay promote nerve cells to secrete excessive IL-1βand IL-6.
Effect of nicotine on hippocampal cultures counteracting Aβneurotoxicity:In the normal control group,fluorescence stains of the neuron were even,neuronal body was full, cell contour was smooth and round,and nerve processes formed a network.In the nicotine AD group,fluorescence stains of the neuron were similar to those of normal neurons, neuron body was full,cell contour was smooth and round,nerve processes grew like normal ones,neuron body diameter and process length were near to those of normal neurons.In the Aβgroup,the number of neurons was small,some cells detached from the bottom wall and floated in the medium,damaged neurons degenerated gradually,cell body was swollen,and there were sediments,ruptured nerve processes,and disintegrated neurons.Moreover, neuron body diameter was increased,while nerve processes shortened.
MTT assay of cell proliferation and viability:Cell viability was 54.7%and 62.7%in the nicotine(10uM) +Aβgroup and the nicotine(20uM) +Aβgroup respectively,but only 29.57%in the Aβgroup,suggesting that nicotine may counteract the neurotoxicity of Aβ, increase cell viability,and protect neurons.
Conclusions
Oral administration of nicotine dissolved in drinking water simulated spontaneous smoking well in terms of nicotine absorption and drug action.The nicotine AD rat models were established by injecting Aβ_(25-35) in bilateral hippocampus after certain periods of oral administration of nicotine.
During the Morris water maze test,the latency in the place navigation test was prolonged in the nicotine AD group as compared to the normal control group,but was significantly shortened compared to the AD group.In the spatial exploration test,the percentages of swimming time and distance at each quadrant were significantly increased in the nicotine AD group than in the AD group.These findings suggest that nicotine may prevent and treat cognitive disorder of AD rats.
It was found that oral nicotine may increase expression ofα7nAChR,attenuate Aβ-reduced reduction ofα7nAChR and suppress Aβ_(25-35)-induced activation of microglial cells and astrocytes,thus reducing secretion of IL-1βand IL-6 by glial cells.Nicotine, mediated by microglial cellα7nAChR,suppresses secretion of IL-1βand IL-6,and thus exerts its anti-inflammatory effect.
As revealed in the mixed hippocampal cultures,nicotine may counteract Aβ_(25-35) cytotoxicity.Following nicotine pretreatment,the secretion of IL-1βand IL-6 by glial cells was suppressed,the neurotoxicity of Aβ_(25-35) to neurons was decreased,resulting higher cell viability;moreover.
AD的特征性病理改变是老年斑(SP)、神经原纤维缠结(NFT)、神经元颗粒空泡变性、脑血管淀粉样变性等。由于AD的确切病因和发病机制并不完全清楚,因而在临床缺乏对AD明确有效的治疗措施。近年来的研究表明,大脑局部过度的炎性反应引起大量的细胞因子释放,在AD的发生和发展中起重要作用。炎性反应同老年斑和神经原纤维缠结为AD的主要特征。针对AD的病理特点,我们认为阻断AD的炎性反应是一治疗靶点。
β-淀粉样蛋白(Aβ)可激活小胶质细胞导致炎性细胞因子IL-1β、IL-6、TNF-α等的分泌增加,小胶质细胞分泌的IL-1β又刺激星形胶质细胞活化,活化的星形胶质细胞进一步分泌炎性细胞因子,加重Aβ的沉积,从而形成“恶性循环”,导致神经元和突触的不可逆损害,出现神经病理和临床改变。
人们开始用非甾体抗炎药(NSAIDs)治疗AD。研究表明,长期应用NSAIDs可以降低AD发病的危险性并可缓解AD的症状。故抗炎治疗可以延缓AD的发生,缓解AD的临床症状。研究证实烟碱可抑制机体的炎性反应。给实验动物注射烟碱,炎性反应减轻。有学者经过流行病学研究,提出吸烟可降低AD发病的危险性。给AD患者使用烟碱透皮贴剂,认知功能得到改善。
烟碱在中枢神经系统的受体是胶质细胞、神经元表面的α7nAChR,胶质细胞是中枢神经系统内分泌炎性介质的主要细胞。我们这项研究的目的是探讨在AD大鼠内,烟碱作用于胶质细胞表面的α7nAChR对抗Aβ引起的炎性反应,研究烟碱对AD大鼠认知功能改善的作用机制。
我们给予AD模型大鼠口服烟碱,通过Morris水迷宫实验,并检测α7nAChR、IL-1β、IL-6等的变化,观察烟碱对AD大鼠认知功能的改善作用,探讨烟碱的作用机制。在海马神经组织细胞混合培养体系中加入烟碱和Aβ_(25-35),检测炎性细胞因子IL-1β、IL-6变化,探讨Aβ_(25-35)对神经元的损害作用,烟碱的抗炎效应和对神经细胞的保护作用。
主要研究内容和结果:
1.烟碱对AD大鼠海马炎性反应的作用
动物实验分三组,烟碱AD组、AD对照组、正常对照组。给予S-D大鼠口服烟碱,然后在大鼠双侧海马区注射Aβ_(25-35),建立烟碱AD大鼠模型。给S-D大鼠双侧海马区注射Aβ_(25-35),建立AD大鼠模型。
通过Morris水迷宫实验,检测烟碱AD组、AD组大鼠和正常对照组大鼠学习记忆能力的变化。烟碱AD组大鼠在平台定位航行实验中潜伏期较正常对照组有所延长,在平台象限的游泳时间百分比和游泳距离百分比较正常对照组降低,但高于AD对照组,差异明显。AD组大鼠平台定位航行实验潜伏期虽有下降趋势,但不稳定,在平台象限搜索次数较少,目的性不明确,与烟碱AD组、正常对照组相比差异明显。对三组动物进行方差分析,差异具有显著意义。
对海马组织α7nAChR蛋白含量进行检测,AD组第1天、第7天、第15天α7nAChR蛋白明显下降,与正常对照组相比,差异显著。烟碱AD组第1天、第7天、第15天下降,但下降幅度不如AD组明显,与AD组相比,存在差异;与正常组相比,无差异。
AD组海马组织IL-1β、IL-6在1-15天明显升高,第7天达峰值,第15天仍明显高于正常对照组。烟碱AD组IL-1β、IL-6升高,但与AD组相比,升高幅度不大,存在显著性差异;与正常对照组相比,存在差异。
α7nAChR免疫染色阳性细胞:α7nAChR免疫染色阳性物质位于细胞膜和细胞突起。正常对照组α7nAChR免疫阳性物质染色深,阳性细胞排列规则、密集。烟碱AD组,α7nAChR免疫阳性物质染色较深,阳性细胞排列比较有规则,接近正常对照组。AD组α7nAChR免疫染色略浅,阳性细胞排列欠规则。
IB4免疫染色阳性小胶质细胞:IB4免疫染色阳性物质位于整个细胞区域。正常对照组海马区IB4免疫染色阳性细胞数目少、染色浅,胞体扁长,分支细、短;烟碱AD组:海马区IB4阳性细胞数较正常组增多,染色浅,胞体形态与正常组类似;AD组:海马区IB4免疫染色阳性细胞数目明显增多,胞体增大,突起增长增粗,部分IB4阳性细胞呈灌木样或杆状。
GFAP免疫染色阳性星形胶质细胞:GFAP免疫染色阳性物质位于整个细胞区域。正常对照组海马区GFAP免疫染色阳性细胞数目少,染色淡而均匀,胞体小,突起细短;烟碱AD组海马区GFAP免疫染色阳性细胞数目增多,染色加深,部分细胞胞体增大,突起增长;AD组海马区GFAP免疫染色阳性细胞明显增多,胞体增大,突起增长增粗。
IL-1β免疫染色阳性细胞:IL-1β免疫染色阳性物质主要位于细胞体。正常对照组、烟碱AD组大鼠海马区IL-1β免疫染色阳性物质反应弱,染色浅。AD组海马区域IL-1β免疫染色阳性增强,阳性细胞增多。
2、烟碱抗Aβ_(25-35)神经毒性作用研究
用2d龄Sprague-Dawley大鼠海马神经组织细胞混合培养体系。实验分为:正常对照组、Aβ(2μM)组、烟碱(10μM)+Aβ(2μM)组、烟碱(20μM)+Aβ(2μM)组。
无菌分离海马组织,培养海马神经组织细胞混合体系,到第5天,在相差显微镜下观察,培养细胞生长良好,细胞扁平,神经元四周出现明显光晕,胞体增大,突起长出并逐渐伸长,部分联成网络。分别按10μM、20μM浓度加入烟碱,孵育1h后加入Aβ(2μM),再孵育24小时。检测细胞培养上清液IL-1β、IL-6含量,测定神经元胞体直径和突起长度及细胞生存率。
烟碱Aβ组细胞培养上清液中IL-1β、IL-6含量增高,烟碱浓度10uM时细胞培养上清液中IL-1β、IL-6含量与正常对照组相比差异明显,而烟碱浓度在20uM时细胞培养上清液中IL-1β、IL-6含量与正常对照组相比差异不明显。烟碱Aβ组两种浓度下,细胞培养上清液中IL-1β、IL-6含量与Aβ组相比,差异显著。
神经元荧光染色,正常对照组神经元胞体饱满,细胞轮廓圆滑,神经突起形成网络联系;烟碱Aβ组,神经元细胞形态接近正常,神经元胞体直径和突起长度与正常组相差不明显;Aβ组,神经元数目减少,部分细胞脱离底壁而漂浮,损伤神经元逐渐退化、崩解,出现沉淀,神经突起断裂,神经元胞体直径增大,胞体肿胀,突起回缩。
烟碱(10μM)+Aβ(2μM)组、烟碱(20μM)+Aβ(2μM)组细胞存活率分别为54.7%、62.27%。而Aβ组细胞存活率只有29.57%。烟碱具有抗Aβ神经毒性,提高细胞生存率,保护神经元的作用。
结论
大鼠口服烟碱后,在其双侧海马区注射Aβ_(25-35),成功建立了烟碱AD大鼠模型。
在Morris水迷宫实验中,烟碱AD组大鼠平台定位航行实验的潜伏期比正常对照组有延长,但比AD大鼠明显缩短;在空间探索实验中,烟碱AD组大鼠平台象限游泳时间百分比、游泳距离百分比较AD组大鼠明显增高。证实烟碱可改善AD大鼠认知功能。
烟碱AD组与AD组比较,海马小胶质细胞和星形胶质细胞的活性降低,IL-1β、IL-6分泌减少,α7nAChR下降不明显。在α7nAChR介导下,烟碱抑制了胶质细胞的炎性细胞因子IL-1β、IL-6分泌,烟碱有明显的抗炎效应,烟碱对神经元具有保护作用。
在海马神经组织细胞混合培养体系中证实烟碱可对抗Aβ_(25-35)的细胞毒性作用。烟碱预处理后,抑制了Aβ_(25-35)诱导胶质细胞分泌IL-1β、IL-6的作用,Aβ_(25-35)对神经元的细胞毒性作用降低,细胞生存率提高。
Alzheimer's disease(AD) is a neurodegeneration disease of the nervous system.AD patients present with impairment in learning,memory and intelligence,and loss of the self-care ability at late stages.Due to aging of the population,AD has become the fourth cause of death of the elderly next to heart disease,tumor and stroke.The treatment and nursing of AD patients are costly,bringing heavy financial burdens to the family and the society as well.
The hallmarks of AD pathology are senile plaques,neurofibrillary tangles, granulovacuolar degeneration of neurons and cerebrovascular amyloidosis.The precise etiology and pathogenesis of AD are unclear;therefore,an effective therapy of AD is not available yet.Recent studies have demonstrated that excessive,regional inflammatory reaction in the brain may cause the release of large amounts of free radicals and cytokines, resulting in the incidence and progression of AD.As with senile plaque(SP) and neurofibrillary tangles(NFTs),inflammatory reaction is also a pathologic hallmark of AD. In light of the pathologic hallmarks of AD,we consider blockage of inflammatory reaction as one of the therapeutic targets for AD.
Aβand neurofibrils may activate microglial cells,leading to enhanced expression of cell surface MHC-Ⅱand increased secretion of inflammatory cytokines such as IL-1β,IL-6 and TNFα.IL-1β,in turn,activates astrocytes,and activated astrocytes secrete more inflammatory cytokines,resulting in Aβdeposition and neurofibrillary tangles;therefore,a vicious cycle forms,which causes irreversible damages to neurons and synapses as well as pathologic and clinical changes of the nervous system.
Inflammatory cytokines resulting from brain inflammation are also trigger factors for brain neuroinflammation.Accordingly,non-steroid anti-inflammatory drugs(NSAIDs) are used to treat AD.It has been shown that the long-term use of NSAIDs may reduce the risk of AD and ameliorate the symptoms of AD patients.Therefor,anti-inflammation therapy can delay the onset of AD as well as improve cognitive function in the aymptoms of AD.
Recent studies suggest that nicotine can inhibbite the inflammation.The rats are chronically administrated with nicotine.Results showed that nicotine can decrease the chemotaxis/chemokinesis of peripheral vlood mononuclear cells,impaire T-help cells antigen present,attenuate T-cell activation.Nicotine-treatment decrease T-cell proliferation, inhibite the migration of leukocytes,attenuates the plasma effusion induced inflammation.
Smoking may also reduce the risk of AD.Treatment with nicotine transdermal patches may improve the intelligence of AD patients as revealed by the Coruner's continuous performance test(CPT).There is a cholinergic anti-inflammatory pathway in the body, through which acetylcholine or nicotine may reduce lipopolysaccharide-induced release of inflammatory cytokines such as TNF-α,IL-1βand IL-6 viaα7nAChR on macrophages and thus lessen lipopolysaccharide-induced inflammatory response.Since neurons,microglial cells and astrocytes expressα7nAChR in the central nervous system,is there a similar cholinergic anti-inflammatory pathway in the central nervous system?
Acute treatment of ex vivo microglial cells with nicotine may reduce LPS-induced secretion of TNF-α.Nevertheless,the effect of nicotine on Aβactivated microglial cells, secretion of IL-1βand IL-6 has not been reported yet.
In the study,we administered AD model rats with nicotine orally,and detected the changes in the contents ofα7nAChR,IL-1β,and IL-6,so as to observe the effect of nicotine on cognition and release of inflammatory cytokines.Nicotine and Aβwere added into the mixed nerve cell cultures,and the protective effect of nicotine on neurons was observed; meanwhile,the changes in IL-1 and IL-6 were detected,so as to further elucidate the anti-inflammatory effect of nicotine.
Main contents and results:
1.Effect of nicotine on Aβ-induced inflammatory reaction in the nervous system
S-D rats were orally administered with nicotine to perform nicotine pretreatment.Then, Aβ25-35 was injected into bilateral hippocampus to establish the nicotinic AD rat model and the AD control rat model.The differences in learning and memory among the AD nicotine rats,AD rats and normal rats were observed by the Morris water maze test.
During the place navigation test,the latency was longer in the nicotine AD group than in the normal control group,and the percentages of swimming time and swimming distance at each quadrant were lower in the nicotine AD group than in the normal control group,but were still significantly higher than in the AD control group.In the AD control group,the latency tended to decrease,but was not stable,and the frequency of search at each quadrant was low and the purposiveness was not clear,and there were significant differences in the regards between the nicotine AD group and the normal control group.Compared to the normal control group,rats of the nicotine AD group presented with certain impairment of intelligence,but the impairment was significantly milder than that in the AD group. Variance analysis revealed significant differences among the three groups of animals.
Western blot analysis ofα7nAChR protein in hippocampal tissue revealed thatα7nAChR protein content was decreased slightly in the nicotine AD group at days 1,7 and 15 after injection of Aβ(P＜0.05 at day 1),and there were no significant differences between the nicotine AD group and the normal control group.However,in the AD group,α7nAChR protein content was decreased at days 1,7 and 15 after injection of Aβand existed till day 15,and there were significant differences between the nicotine AD group and the normal control group.
α7nA ChR immunoreactive cells:In the normal control group,cells were darkly stained and well-arranged in great density.In the nicotine AD group,cells were stained relatively darkly and arranged relatively well,just similar to cells of the normal control group.However,in the AD group,cells were faintly stained and arranged in mess.
The levels of IL-1βand IL-6 in the hippocampal tissue:ELISA results indicated that IL-1βand IL-6 contents of hippocampal tissue were low in the normal control group and increased slightly in the nicotine AD group following injection of Aβ(the contents were the highest at day 1 and then decreased gradually),and there were no significant differences between the nicotine AD group and the normal control group.However,in the AD group, IL-1βand IL-6 contents increased drastically and reached a peak at day 7 and then decreased,but the contents were still significantly higher than those in the normal control group and the nicotine AD group at day 15.
IL-1βimmunoreactive cells:In the hippocampus of rats of the normal control group and the nicotine AD group,IL-1βimmunoreactivity was weak and cells were faintly stained; however,in the AD group,IL-1βimmunoreactivity was strong and cells were darkly stained.
IB4 immunoreactive microglial cells:In the normal control group:the number of IB4 immunoreactive hippocampal cells was small;cells were faintly stained,with flat and long body and short and thin processes.In the nicotine AD group:the number of IB4 immunoreactive hippocampal cells was increased compared to the normal group,and cells were faintly stained with similar morphology with cells of the normal group.In the AD group:The number of IB4 immunoreactive hippocampal cells was significantly increased, and cell body size was increased,with prolonged and thickened processes.Some of the IB4 immunoreactive cells were of shrub- or rod-shape.
GFAP immunoreactive astrocytes:In the normal control group:the number of GFAP immunoreactive hippocampal cells was small,cells were faintly and evenly stained,cell body size was small,and nerve processes were thin and short.In the nicotine AD group:the number of GFAP immunoreactive hippocampal cells was increased,cells were darkly stained,the body size of some cells was increased,and nerve processes were prolonged.In the AD group:The number of GFAP immunoreactive hippocampal cells was significantly increased,the size of cell body was increased,and nerve processes were thickened.
2.Counteraction of nicotine against Aβ_(25-35) neurotoxicity
The mixed hippocampal cells of 2d-old Sprague-Dawley rats were cultured.There were four groups:the normal control group,Aβ(2μM) group,the nicotine(10μM) +Aβ(2μM) group and the nicotine(20μM)+Aβ(2μM) group.
Hippocampal tissue was isolated under sterile condition,and mixed hippocampal nerve cells were cultured.At day 5 of culture,cells were observed under phase-contrast microscope.Cells grew well,cell body was flat,with marked halos around,body size was increased,and nerve processes were long and extended gradually,forming a network.The hippocampal cultures incubation with differentia concentration nicotine for 1h prior to treatment with Aβ_(25-3).After 24h incubation of cells with various concentrations of nicotine or nicotine +Aβ,IL-1βand IL-6 contents in culture supernatants were determined by ELISA and neurons were subjected to fluorescence staining,followed by determination of neuron body diameter and process length as well as cell viability assessment by the MTT assay.
IL-1βand IL-6 contents in culture supernatants:In the nicotine Aβgroup,IL-1βand IL-6 contents were increased mildly after addition of Aβ;the differences in IL-1βand IL-6 contents were not significant between the nicotine Aβgroup and the normal control group, but were significant between the nicotine Aβgroup and the Aβgroup,suggesting that nicotine has inhibitory effect on Aβ-induced release of IL-1βand IL-6.Provided with a constant Aβconcentration,the inhibitory effect was related to the nicotine concentration.In the Aβgroup,IL-1βand IL-6 contents in culture supernatants were significantly higher than those in the nicotine Aβgroup and the normal control group,confirming that Aβmay promote nerve cells to secrete excessive IL-1βand IL-6.
Effect of nicotine on hippocampal cultures counteracting Aβneurotoxicity:In the normal control group,fluorescence stains of the neuron were even,neuronal body was full, cell contour was smooth and round,and nerve processes formed a network.In the nicotine AD group,fluorescence stains of the neuron were similar to those of normal neurons, neuron body was full,cell contour was smooth and round,nerve processes grew like normal ones,neuron body diameter and process length were near to those of normal neurons.In the Aβgroup,the number of neurons was small,some cells detached from the bottom wall and floated in the medium,damaged neurons degenerated gradually,cell body was swollen,and there were sediments,ruptured nerve processes,and disintegrated neurons.Moreover, neuron body diameter was increased,while nerve processes shortened.
MTT assay of cell proliferation and viability:Cell viability was 54.7%and 62.7%in the nicotine(10uM) +Aβgroup and the nicotine(20uM) +Aβgroup respectively,but only 29.57%in the Aβgroup,suggesting that nicotine may counteract the neurotoxicity of Aβ, increase cell viability,and protect neurons.
Conclusions
Oral administration of nicotine dissolved in drinking water simulated spontaneous smoking well in terms of nicotine absorption and drug action.The nicotine AD rat models were established by injecting Aβ_(25-35) in bilateral hippocampus after certain periods of oral administration of nicotine.
During the Morris water maze test,the latency in the place navigation test was prolonged in the nicotine AD group as compared to the normal control group,but was significantly shortened compared to the AD group.In the spatial exploration test,the percentages of swimming time and distance at each quadrant were significantly increased in the nicotine AD group than in the AD group.These findings suggest that nicotine may prevent and treat cognitive disorder of AD rats.
It was found that oral nicotine may increase expression ofα7nAChR,attenuate Aβ-reduced reduction ofα7nAChR and suppress Aβ_(25-35)-induced activation of microglial cells and astrocytes,thus reducing secretion of IL-1βand IL-6 by glial cells.Nicotine, mediated by microglial cellα7nAChR,suppresses secretion of IL-1βand IL-6,and thus exerts its anti-inflammatory effect.
As revealed in the mixed hippocampal cultures,nicotine may counteract Aβ_(25-35) cytotoxicity.Following nicotine pretreatment,the secretion of IL-1βand IL-6 by glial cells was suppressed,the neurotoxicity of Aβ_(25-35) to neurons was decreased,resulting higher cell viability;moreover.
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