西酞普兰对全脑缺血VD大鼠神经发生的影响及5-HT_（1A）受体机制初探
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摘要
血管性痴呆(VD)是仅次于阿尔采默病(AD)引起老年期痴呆的常见病因,严重危害老年人生存质量,但迄今还没有治疗VD的有效方法。VD大多由于脑血流量明显减低导致的脑灌注不足所致,对缺血缺氧非常敏感的海马在VD的认知功能障碍的发生发展中起重要作用。由于大量研究证实成年脑内存在具有增殖与分化潜能的神经干细胞(NSCs),比如海马齿回(DG)和室下区(SVZ)等,尤其是海马NSCs的增殖、分化、迁移和整合因与学习记忆过程密切相关,给治疗VD带来了新的希望。近来研究发现,脑缺血可以激活脑内NSCs增殖、迁移和分化,但是脑缺血后增强的神经发生并不能代偿因缺血而造成的神经元丢失和海马的学习记忆功障碍,所以目前创造合适的微环境,进一步激活自身的NSCs和内源性修复已成为一个重要的研究方向。在这一方面,5-HT和选择性中枢5-HT再摄取抑制剂(SSRIs)类药物倍受关注。此外研究发现,5-HT1A受体不仅在海马含量丰富,而且是5-HT介导神经发生的主要受体。尽管如此,目前仍缺乏有关SSRIs对脑缺血神经发生及认知障碍作用及作用机制的研究。
基于上述理由,我们假设:SSRIs类药物西酞普兰(CIT)可促进VD大鼠脑内NSCs增殖及分化,并进而改善大鼠认知功能,而且此过程受到5-HT1A受体功能的调控。本研究可为脑缺血海马神经发生的调控提供重要的实验依据,也可为临床干预脑缺血性认知功能障碍提供新的思路。
研究目标:
1.阐明VD大鼠脑内神经干细胞增殖的时空关系;
2.明确CIT对脑内不同部位NSCs增殖和分化的作用及其对大鼠认知功能的影响;
3.初步阐明CIT促脑缺血神经发生及影响认知功能的机制:5-HT及5-HT1A受体的作用探讨。
研究方法:
1.动物分组及处置:Wistar大鼠(n=336)随机分为正常正常对照组(NC)、假手术对照组(SC)、血管性痴呆组(VD)、西酞普兰干预的血管性痴呆组(VD-C)以及西酞普兰和WAY100635联合干预组(VD-CW),后四组按手术后时相点每组分术后1、3、7、14、21、42d组。CIT 20mg/kg、WAY100635 0.3mg/kg腹腔注射,1次/d,21天后造模,造模后持续给药至相应时相点。BrdU 50mg/kg腹腔注射,每天1次,第7次注射后12h处死动物用于NSCs增殖的研究;对各实验组术后14d亚组,每天1次,第7次注射后28d处死大鼠用于NSCs分化的研究。采用改良的Pulsinelli’s四血管阻断法制作VD动物模型
2.动物认知功能检测:Morris水迷宫定位航行实验和空间搜索实验检测平均逃逸潜伏期(EL)、平台象限游泳距离百分比(DP)和穿越平台次数反映大鼠空间学习和记忆功能;大鼠电生理检测类P3波潜伏期(类P3L)。
3. NSCs增殖的观察:采用免疫组织化学方法, 35μm新鲜冰冻切片0.3%TritonX-100和2N HCl处理后,SABC法Cy3免疫荧光或DAB显色后,显微镜下观察拍照。
4. NSCs分化的观察:采用BrdU免疫荧光双标记的方法,BrdU免疫荧光标记后,分别加GFAP或Tuj-1或Calbindin-D28k抗体,各自标记星形胶质细胞、幼稚和成熟神经元及成熟神经元,另一荧光显色系统显色后,倒置荧光显微镜或激光共聚焦显微镜下观察拍照。
5.尼氏染色检测海马CA1神经元存活情况。
6. 5-HT1A受体表达测定:采用实时荧光定量PCR(RT-PCR)法,上游引物5'–GCCCCCCAAGAAGAGCCTGA–3',下游引物5'–GCCATCTTGCGCTTTGCTTC– 3'。内参照物GAPDH上游引物:5'–ACCACAGTCCATGCCATCAC–3',下游引物5'–TCCACCACCCTGTTGCTGTA–3'。先后进行总RNA提取,逆转录反应及实时荧光定量PCR扩增。以相对表达丰度反映5-HT1A受体mRNA表达。
7.高效液相色谱(HPLC)检测海马和皮层神经递质的含量。
8.细胞计数及统计学处理:形态学研究组织切片均在同一放大倍数下分析(免疫组织和免疫荧光化学200×,组织化学400×),应用IPP 6.0图像分析软件进行分析。所有数据资料均以均数±标准差(ˉx±s)表示,采用SPSS 11.0统计软件进行分析。
实验结果
1.各实验组大鼠脑内NSCs增殖的时空分布: NC组大鼠脑内海马DG和SVZ区BrdU阳性细胞分布最显著,在皮层也有少量表达。大鼠海马DG细胞增殖从全脑缺血后3d开始明显增加,术后14d达高峰(BrdU阳性细胞数约为缺血前的3倍)。VD-C组各时相点海马DG细胞增殖数量从术后3d开始约为VD组的2倍。但VD-CW组DG细胞增殖受到显著抑制,且较VD组和VD-C组细胞增殖明显减少,其差别有统计学意义。
NC及SC组大鼠CA1区、CA2和CA3区均未见BrdU阳性细胞,脑缺血后海马CA1和CA2区增殖细胞出现时间较晚,缺血后7d才有BrdU阳性表达,且数量较少。加用CIT后可使CA1区细胞增殖增加约1倍,CA2区细胞增殖提前到缺血3d开始出现且较高表达持续到术后21d。但联合应用WAY 100635后逆转了CIT增强的CA1和CA2区的细胞增殖。
VD组术后3d SVZ神经发生开始显著增强,加用CIT后神经发生的明显增强提前到术后1d。术后7d BrdU阳性表达至峰值(与术后3d组比较P<0.01),此后迅速下降(术后14d与7d比较差异显著,P<0.01),14d后下降趋势减缓。VD-C组各时相点BrdU表达情况与VD组比较无显著差异,而VD-CW组各时相点神经发生与VD-C组比较无显著差异。缺血后各实验组PCg和Str18区BrdU阳性表达增加。VD组术后1~3d皮层Ⅱ~Ⅵ层大脑皮质BrdU阳性表达开始增加,术后7d BrdU阳性表达较缺血3d明显增加(P<0.01),缺血14d增加更为显著(P<0.01),缺血21d BrdU阳性表达显著减少。VD-C组术后各时相点的皮层BrdU阳性表达较VD组明显增加(P<0.01),术后14d尤其显著。VD-CW组缺血各时相点BrdU阳性细胞数较VD组明显增加,但与VD-C组比较无显著差异。
2.各实验组大鼠脑内NSCs存活分化的情况:
脑缺血再灌注各实验组均可见双标记阳性细胞。①在海马DG,VD组新生细胞存活率较SC组显著下降,但双标记阳性细胞比率较SC组显著增高(P<0.05),其BrdU阳性细胞主要分化为Tuj-1阳性的不成熟神经元;CA1区BrdU阳性细胞主要表达Tuj-1和Calbindin-D28k标志物;BrdU/GFAP双标记阳性细胞散在分布于齿回GCL和海马门区。VD-C组新生细胞存活率成神经分化的比例增加,其海马DG和CA1区分化为Calbindin-D28k阳性成熟神经元的比例较VD组增加,但BrdU/GFAP双标记阳性率无明显改变。在VD-CW组则发现新生细胞存活和分化的比例显著降低,少见BrdU/Calbindin-D28k双标记阳性细胞。②皮层BrdU阳性细胞出现在PCg区、Str18区、PAC区等部位,以PCg区BrdU阳性表达最稳定。VD组BrdU阳性细胞存活率较SC组降低,但无统计学差异;VD-C组新生细胞存活率较VD组明显增高(P<0.05)。NS和SC组未发现双标记阳性细胞,VD组可见少量BrdU/Tuj-1和BrdU/Calbindin-D28k双阳性表达,较多BrdU阳性细胞表达GFAP。VD-C组BrdU/Tuj-1双阳性率与VD组比较无显著差异,但BrdU/Calbindin-D28k双阳性表达百分率较VD组显著升高(P<0.01),且细胞突起较长。虽然VD-CW组各项指标均较VD-C组降低,但差异无显著性。
3.海马5-HT1AR mRNA RT-PCR测定结果:
术后1d,各组5-HT1AR mRNA表达显著下调(P<0.01),术后3d开始回升,VD组海马5-HT1A受体mRNA表达在术后14d达到其峰值。和VD组比较,VD-C组除术后1d组外其余各组大鼠海马5-HT1A受体mRNA表达到丰度均显著升高(P <0.01),其表达峰值提前至术后7天,且一直到术后21d仍维持在相对较高水平。在CIT联合应用WAY100635的VD-CW组,5-HT1A受体mRNA的表达丰度从术后3d开始仍较VD组高,其中术后3d和7d亚组与VD组有显著差异;但VD-CW组术后各时相点5-HT1A受体mRNA的表达丰度均较VD-C组显著降低。
4.皮层和海马单胺类神经递质5-HT、DA和NE的HPLC检测结果
在海马:大鼠全脑缺血再灌注后7d 5-HT、DA和NE水平均降低,但其中NE水平的下降无统计学意义。VD组到术后21d海马单胺类神经递质水平接近正常。VD-C组大鼠海马5-HT水平升高近1倍(P <0.01),DA和NE水平无明显变化。VD-CW组5-HT水平虽较VD-C组有升高但无显著差异,DA和NE水平亦无显著变化。在皮层:大鼠全脑缺血再灌注后7d 5-HT水平下降,但DA和NE水平无明显变化,术后21d时均接近正常水平。VD-C组5-HT和NE水平与VD组比较无显著变化,但DA水平则较VD组明显升高(P <0.05)。VD-CW组皮层5-HT水平上升明显(约为SC的3倍),皮层DA水平较VD-C组明显下降(P <0.01),而NE水平无明显变化。
5.海马CA1区神经元存活情况:
各实验组大鼠海马CA1区神经元均较SC组显著减少,且均在术后7d程度最严重,此后海马CA1区神经元数量开始逐渐恢复。其中,VD-C组恢复的趋势较VD组明显,而VD-CW组的恢复趋势最为缓慢。各实验组海马CA1区神经元减少的程度不同:和VD组比较,VD-C组术后各时相点CA1区神经元均较多,且差异显著(P <0.01);而VD-CW组的CA1区神经元数量却较少,除了7d和14d组差异显著性在P <0.05外,其余各时相点的差异均非常显著(P <0.01)。
6.大鼠Moris水迷宫行为学检测结果:
VD、VD-C和VD-CW组大鼠定位航行实验平均逃逸潜伏期(EL)在造模后均较NC及SC组显著延长(P<0.01),其后随时间推移逐渐缩短;但VD-C组EL延长程度较VD组减轻,且组术后14d、21d和42d的EL延长较VD组显著减少(P<0.05);相反,VD-CW组EL较VD组各14d、21d、42d亚组EL均显著延长。
VD、VD-C和VD-CW组大鼠空间搜索实验平台象限游泳距离百分比(DP)造模后均显著降低,但随时间推移逐渐上升;VD-C组DP均较VD组高(P <0.05),到术后42d已经与SC组物显著差异;相反,VD-CW组造模后各时相点DP均较VD组相应时相点明显减低(7d组P<0.05,14d、21d、42d亚组P<0.01)。大鼠穿越目标区的次数与DP的变化具有相同的趋势。
7.事件相关电位类P3检测结果:
各实验组除VD-C组术后42d亚组外,各时相点类P3L均较SC组显著延长。各实验组大鼠术后3d与术后1d亚组比较类P3L显著延长,术后7d类P3L进一步延长,其延长的程度在VD组和VD-C组无统计学意义,但在VD-CW组则显著延长。此后类P3L延长的程度随时间延长逐渐减轻,但减轻的程度不同:VD组和VD-CW组到术后42d类P3L才显著缩短;而在VD-C组,术后21d即较14d明显改善,术后42d的P3L较21d显著缩短且与SC组比较已经无显著差异。
研究结论:
1.全脑缺血再灌注可诱导成年大鼠脑内神经发生增强,以海马DG和SVZ区新生神经细胞的增殖最明显,海马CA1、CA2区和PCg皮层也发现脑缺血后神经发生增强的现象。海马和皮层增强的神经发生在术后14d达高峰,21d开始下降,一直可持续到术后42d;而SVZ神经发生的高峰出现在术后7d。大鼠脑缺血再灌注后水迷宫和类P3认知功能的改变,与海马及皮层BrdU阳性细胞的增殖没有相关性。
2. CIT可显著促进VD大鼠海马DG、CA1、CA2区和皮层的BrdU阳性细胞增殖,对SVZ区的新生神经细胞增殖无明显影响。同时,CIT可显著促进海马DG、CA1区和皮层新生神经细胞的成神经元分化,并且该作用与CIT改善VD大鼠认知障碍的效应关系密切。CIT的上述作用可被联合应用WAY100635所逆转。
3. CIT促进VD大鼠脑内神经发生的机制,可能与其提高中枢突触间隙5-HT水平、增加海马5-HT1A受体mRNA表达有关;而其改善动物认知障碍的作用,在术后21d内可能与其调节海马及皮层单胺类神经递质水平、保护海马CA1区神经元有关,在术后42d则可能是通过促进海马和皮层新生神经细胞的成神经元分化及神经保护作用实现的。
Vascular dementia (VD) is the second most common form of dementia after Alzheimer's dementia (AD) which seriously interfere the life of aged people. And till now, a restorative treatment has not been reached yet. VD is characterized by loss of neuronal cells especially in hippocampus, a region in the brain that has the ischemic injury vulnerability, and loss of executive function with milder memory loss. There is a growing body of evidence that neural stem cells(NSCs) reside in the adult central nervous system where neurogenesis occurs throughout lifespan. Neurogenesis concerns mainly two areas in the brain: the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ). Since the proliferation, differentiation, migration and integration of NSCs in hippocampus have close relationship with cognitive function, it provides a possible therapeutic strategy for ischemic injury repair. Although there have been consistent reports that cerebral ischemia increases the number of newly generated neurons that migrate from the SGZ into the granular cell layer(GCL) of DG and incorporate into functional synaptic circuitry in adult rats, but this still could not compensate the loss of neurons and the cognitive impairment. So it is becoming more and more important to find out a suitable microenvironment for further improve the neurogenesis triggered by ischemic injury. Fortunately, animal studies have shown strong neurogenetic function of serotonin and selective serotonin reuptake inhibitors (SSRIs) and the serotonin 1A receptor, which is abundant in hippocampus, has major effect during neurogenesis. However, it is yet not known whether SSRIs impact the proliferation and maturation of newborn neurons and the cognitive function of VD rats.
Here in this study, we test our hypothesis that citalopram(CIT), one of SSRIs, could promote neurogenesis and improve cognitive functions in vascular dementia model of rats and it’s action regulated by the function of serotonin 1A receptor. Our research could provide some experimental evidence for the mechanism of ischemic neurogenesis and choice for vascular dementia therapy.
Objective:
1. To interpret the characteristics of NSCs proliferation in vascular dementia model of adult rats.
2. To identify the influence of CIT on NSCs proliferation and differentiation in different region of the brain and on cognitive function of VD rats.
3. To elucidate the role of serotonin 1A receptor in ischemic neurogenesis and CIT effects in our vascular dementia model.
Methods:
1. Animals, drugs and establishment of rat model: Male Wistar rats (n=336) were randomly divided into five groups: normal control group(NC), sham operation control group(SC), transient cerebral ischemic group(VD), citalopram treated transient cerebral ischemic group(VD-C) and VD-CW group which treated with both citalopram and WAY100635. The later four groups were further divided into 1-, 3-, 7-, 14-, 21- and 42-days-post-operation subgroups. And in every subgroup 6 animals were involved. Citalopram(20mg/kg) and WAY 100635(0.3mg/kg) were injected intraperitoneally for 21 days before operation and the treatment proceeded until sacrifaction. BrdU(50mg/kg) was given for 7 days before sacrifaction for cell proliferation study. As for cell differentiation study, BrdU(50mg/kg) was given to 14-day-post-operation in VD, VD-C and VD-CW group, and rats were sacrificed 28 days after. The improved Pulsinelli’s 4-vessle occlusion was used to establish ischemia in rats.
2. Measurement for cognitive function: The water maze task was undertaken. Place navigation test and spatial probe test was to observe rats’spatial learning and memory abilities respectively. The escape latency (EL), distance percentage (DP) and times of passing through the platform were analyzed. And P3-like potential was observed too.
3. Observation for NSCs proliferation: Immunohistochemical-staining was preceded with freezing coronal brain slides of 35μm thick each. After sections were incubated in 0.3%TritonX-100 and 2mol/L HCl and results were shown by SABC-Cy3 or DAB. Sections were examined with an inverted microscope.
4. Observation for NSCs survival and differentiation: Double-label immunofluorescence staining was proceeded. After BrdU immunofluorescence staining, sections were incubated with Tuj1, Calbindin-D28k and GFAP respectively, to label immature, mature neurons and astrocytes, use different fluorescence coloration. And the resulting immunofluorescent signal was viewed under fluorescence microscope and confocal microscopy.
5. Nissl stain was proceeded to analyze the survival of CA1 neurons.
6. The expression of serotonin 1A receptor in hippocampus: After Isolation of total RNA and reverse transcription–PCR , Real-time PCR was preceded. Serotonin 1A receptor primers were 5'-GCCCCCCAAGAAGAGCCTGA-3' and 5'-GCCATCTTGCGCTTTGCTTC-3'. GAPDH was used as reference, and the primers were 5'-ACCACAGTCCATGCCATCAC-3' and 5'-TCCACCACCCTGTTGCTGTA-3'。
7. high-performance liquid chromatography(HPLC) was used to detect monoamine neurotransmitters in hippocampus.
8. Cell counting and statistical analysis: Cells were counted under high power (20×or 40×objective) on Olympus microscope with magnifying digital camera. Data analyzed by IPP 6.0 software. All the data are presented as the means±S.E.M. of the individual values for each rat in all groups. Statistical analysis of the data was performed using one-way ANOVA for multiple comparisons.
Results
1. The characteristics of NSCs proliferation in vascular dementia model of adult rats.
BrdU positive cells were observed mainly in dentate gyrus and SVZ and less expressed in cortex in normal rats.
In DG, BrdU-positive cells were gradually increased from 3 days after operation and reached its peak 14 days after operation with the cell number triple as much as that before ischemia. And the number of newly proliferated cells in VD-C group was twice as much as that in VD group from 3 days after ischemia. And in VD-CW group, the proliferation of NSCs was significantly decreased.
There was no BrdU-positive cells in CA1, CA2 and CA3 in normal rats. And NSCs cells were found in CA1 and CA2 7 days after operation, cell proliferated later and less than that in DG. By use of CIT, CA1 cell proliferation increased twice as that in VD group and CA2 cell proliferation was found 3 days after ischemia and continued 21 days after operation. But the cell proliferation was significantly down-regulated in VD-CW group compared with VD-C group.
In SVZ region, cell proliferation obviously up-graded from 3-day-after operation, and it was significantly further enhanced by use of CIT. In every experimental groups, number of BrdU-positive cells 7 days post-ischemia groups was significantly higher than that in 3 days post-ischemia groups(P<0.01). But after that, cell proliferation down-regulated rapidly with significant difference between 14 days to 7days post-ischemia(P<0.01). There was no obvious difference of BrdU-positive cell numbers between VD-C group and VD or VD-CW group.
Number of BrdU-positive cells began to rise in cortex PCg and Str18 area in all experimental groups after ischemia. In VD group, BrdU-positive cells emerged inⅡ~Ⅵlayer of cortex began to rise from 1~3 days post operation and obviously higher 7 days and 14 days after ischemia(P<0.01). Then the number significantly went down 21 days after operation. Number of BrdU-positive cells in VD-C group was much higher compared with VD group(P<0.01) and difference was most obvious 14 days after operation. In VD-CW group, BrdU-positive cells were higher than VD group but had no significant difference with VD-c group.
2. The survival and differentiation of newly generated cells:
Double labeled cells could be found in every experimental group after operation.①In DG, NSCs survival rate of VD group was lower than that in SC group but the percentage of double-labeled cell significantly higher(P<0.05). In group of VD, the BrdU-positive cells mainly differentiated into Tuj1-positive immature neurons in DG and into both immature and mature neurons with positive stain of Calbindin-D28k in CA1. And the BrdU-and-GFAP- positive cells scattered in GCL of DG and hilus. In VD-C group, newly generated cells in DG and CA1 differentiated into mature neurons obviously more than that in VD group and also had higher survival rate. And in VD-CW group, double positive of BrdU/Tuj1 and BrdU/Calbindin-D28k cell percentages were significantly decrease.②In the cortex, the BrdU-positive cells expressed relatively stable in PCg than in Str18 and PAC. NSCs’survival rate of VD group was lower than that in SC group with no significant difference. Survival rate of BrdU-positive cells in VD-C group was much higher than in VD group(P<0.05). Double-positive cell was not found in NS and SC groups but could be found in VD group of which had low percentage of BrdU/Tuj1 and BrdU/Calbindin-D28k staining and relatively high percentage of BrdU/GFAP staining. Compared with VD group, BrdU/Tuj1 double-staining percentage was similar but BrdU/Calbindin-D28k double-staining was much higher(P<0.01) in VD-C group. Although cell differentiation rate was lower in VD-CW group, there was no significant difference.
3. result of RT-PCR examination of serotonin 1A receptor mRNA
One day after transient cerebral ischemia, the relative expression level of serotonin 1A receptor mRNA dropped down obviously in VD, VD-C and VD-CW groups(p<0.01). It began to rise up from 3 days after ischemia. In VD group, the expression level reached its peak 14 days after operation. In, VD-C group, the relative expression levels of serotonin 1A receptor mRNA were much higher (P<0.01) except 1-day-post-ischemia and reached its peak 7 days earlier and continued keep its ascendancy to 21 days after ischemia compared with VD group. In VD-CW group, serotonin 1A receptor mRNA expression was higher than that in VD group from 3 days after operation with significant difference in 3- and 7-day post ischemia, but lower than that in VD-C group.
4. Level of monoamine neurotransmitters in hippocampus detected by HPLC
①In hippocampus: The level of serotonin(5-HT) dopamine(DA) and norepinephrine (NE) were dropped 7 days after cerebral ischemia with significant difference except NE. And the monoamine neurotransmitter returned normal 21 days post-ischemia in VD group. In VD-C group, the level of 5-HT rose twice as much as that in VD group(P<0.01) but the level of 5-HT in VD-CW group rose with no significant difference vs. VD-C group. The level of DA and NE didn’t change either in VD-C or VD-CW group.
②In cortex: The level of 5-HT dropped 7 days after cerebral ischemia with no change of NE and DA and returned normal 21 days post-ischemia. In VD-C group, the level of 5-HT and NE had no statistical difference but the DA level was significantly higher compared with that in VD group(P<0.05). In VD-CW group, the 5-HT level largely rose up, almost triple as much as that in SC group, the level of DA decrease obviously vs. VD-C group(P<0.01), and NE level didn’t change much.
5. Cell survival in CA1
The comparisons indicated that this effect was due to significantly lower cell densities in the ischemic animals as compared to sham-operated (p < 0.001). As compared to sham-operated animals, almost 90% of CA1 pyramidal cells showed signs of neuronal damage 7 days after operation and only regained nearly 65% of CA1 cell number 42 day post-ischemia. In contrast, CIT treated rats had 25% more CA1 neurons than non-treated ischemic rats. But this protective effect was blocked by co-administration of WAY 100635, a specific 5-HT1A receptor antagonist. These results provide evidence that CIT can induce a long lasting (i.e., 6 weeks) hippocampal protection against global cerebral ischemia. And this effect of CIT might be regulated by the function of 5-HT1A receptor.
6. cognitive function examined by Morris water maze test
Results from data analysis indicated that the average escape latency(EL) of all rats in every group was gradually decreased by the increase of trials in the place navigation tests. The EL in the three groups of VD,VD-C and VD-CW were significantly longer than that of the NC and SC groups(P<0.01). The group of VD-C existed longer escape latency(P<0.05), while the EL in this group of 14 days and 21 days after operation were significantly decreased compared with the VD group(P<0.05).In the contrast, after the administration of the WAY100635,he specific inhibitor of 5-HT1AR, the VD-CW rats showed significant longer escape latency.
To test the spatial memory ability, the spatial probe test was performed after the removal of the platform. The data showed that the DP spent in target quadrants had no difference between the NC and SC rats, and the DP of the VD,VD+C and VD+W were respectively decreased significantly. Furthermore, the administration of Citalopram made a better performance in memory compared with other groups(P<0.05) and almost returned to normal 42 days after ischemia. In contrast, the DP decreased sharply compared with VD-7d group(P<0.05) and VD-14, 21, 42d group(P<0.01). There was similar result of times of passing through the platform according to DP.
7. Observation of P3-like latency(P3L)
Except VD-C-42d group, the P3L prolonged significantly in all ischemic groups vs. SC group. The P3L extended largely 3 days than 1day and 7 days than 3 days after ischemia. These extensions had no statistic significance in VD and VD-C groups but really sharply prolonged in VD-CW group. After 7 days of ischemia, the degree of P3L extension extenuated as time goes on with differences in distinct groups. The significant decurtation of P3L did not emerge until 42 days after ischemia in both VD and VD-CW groups. But in VD-C group, the P3L ameliorated from 21 days post-operation and keep on improving to almost normal level 42 days post-operation.
Conclusions
1. Adult brain neurogenesis could be triggered by transient global ischemia. Three days after cerebral ischemia and reperfusion (CIR), enhanced neurogenesis emerged in hippocampus, cortex and SVZ with the most obviously enhancements in DG and SVZ. We found that neurogenesis in CA1, CA2 and PCg could be triggered by ischemia that had seldom been reported. The neurogenesis reached its peak 14 days after operation and decreased from 21-day-post-ischemia till 42 days after ischemia in hippocampus and cortex. And in SVZ, neurogenesis reached its peak 7 days after operation. There was no correlation between changes of cognitive function evaluated by Morris water maze test and P3-like detection and proliferation of BrdU-positive cells in hippocampus and cortex.
2. Chronic administration of CIT (20mg/kg) could obviously enhance BrdU-positive cell proliferation in different brain region of VD rats, areas including DG, CA1, CA2 and cortex, but barely affected the proliferation of newly generated cells in SVZ. Meanwhile, newly generated cells in DG, CA1 and cortex differentiated more into neurons by treatment of CIT and it had close relationship with the curative facts of CIT on cognitive impairments of VD rats. The effects of CIT mentioned above could be reversed by co administration with WAY 100635.
3. The mechanism of neurogenetic effect of CIT in VD rats might be concerned with its function of elevating the 5-HT level in synaptic space in the central nervous system (CNS) and/or of promoting the expression of 5-HT1A receptor mRNA. CIT could ameliorate the cognitive impairment via modulate the CNS levels of monoamine neurotransmitters within 21 days after operation and via neuroprotective effect or promote hippocampus and cortex newly generated cells differentiate into neurons 42 days after ischemia.
基于上述理由,我们假设:SSRIs类药物西酞普兰(CIT)可促进VD大鼠脑内NSCs增殖及分化,并进而改善大鼠认知功能,而且此过程受到5-HT1A受体功能的调控。本研究可为脑缺血海马神经发生的调控提供重要的实验依据,也可为临床干预脑缺血性认知功能障碍提供新的思路。
研究目标:
1.阐明VD大鼠脑内神经干细胞增殖的时空关系;
2.明确CIT对脑内不同部位NSCs增殖和分化的作用及其对大鼠认知功能的影响;
3.初步阐明CIT促脑缺血神经发生及影响认知功能的机制:5-HT及5-HT1A受体的作用探讨。
研究方法:
1.动物分组及处置:Wistar大鼠(n=336)随机分为正常正常对照组(NC)、假手术对照组(SC)、血管性痴呆组(VD)、西酞普兰干预的血管性痴呆组(VD-C)以及西酞普兰和WAY100635联合干预组(VD-CW),后四组按手术后时相点每组分术后1、3、7、14、21、42d组。CIT 20mg/kg、WAY100635 0.3mg/kg腹腔注射,1次/d,21天后造模,造模后持续给药至相应时相点。BrdU 50mg/kg腹腔注射,每天1次,第7次注射后12h处死动物用于NSCs增殖的研究;对各实验组术后14d亚组,每天1次,第7次注射后28d处死大鼠用于NSCs分化的研究。采用改良的Pulsinelli’s四血管阻断法制作VD动物模型
2.动物认知功能检测:Morris水迷宫定位航行实验和空间搜索实验检测平均逃逸潜伏期(EL)、平台象限游泳距离百分比(DP)和穿越平台次数反映大鼠空间学习和记忆功能;大鼠电生理检测类P3波潜伏期(类P3L)。
3. NSCs增殖的观察:采用免疫组织化学方法, 35μm新鲜冰冻切片0.3%TritonX-100和2N HCl处理后,SABC法Cy3免疫荧光或DAB显色后,显微镜下观察拍照。
4. NSCs分化的观察:采用BrdU免疫荧光双标记的方法,BrdU免疫荧光标记后,分别加GFAP或Tuj-1或Calbindin-D28k抗体,各自标记星形胶质细胞、幼稚和成熟神经元及成熟神经元,另一荧光显色系统显色后,倒置荧光显微镜或激光共聚焦显微镜下观察拍照。
5.尼氏染色检测海马CA1神经元存活情况。
6. 5-HT1A受体表达测定:采用实时荧光定量PCR(RT-PCR)法,上游引物5'–GCCCCCCAAGAAGAGCCTGA–3',下游引物5'–GCCATCTTGCGCTTTGCTTC– 3'。内参照物GAPDH上游引物:5'–ACCACAGTCCATGCCATCAC–3',下游引物5'–TCCACCACCCTGTTGCTGTA–3'。先后进行总RNA提取,逆转录反应及实时荧光定量PCR扩增。以相对表达丰度反映5-HT1A受体mRNA表达。
7.高效液相色谱(HPLC)检测海马和皮层神经递质的含量。
8.细胞计数及统计学处理:形态学研究组织切片均在同一放大倍数下分析(免疫组织和免疫荧光化学200×,组织化学400×),应用IPP 6.0图像分析软件进行分析。所有数据资料均以均数±标准差(ˉx±s)表示,采用SPSS 11.0统计软件进行分析。
实验结果
1.各实验组大鼠脑内NSCs增殖的时空分布: NC组大鼠脑内海马DG和SVZ区BrdU阳性细胞分布最显著,在皮层也有少量表达。大鼠海马DG细胞增殖从全脑缺血后3d开始明显增加,术后14d达高峰(BrdU阳性细胞数约为缺血前的3倍)。VD-C组各时相点海马DG细胞增殖数量从术后3d开始约为VD组的2倍。但VD-CW组DG细胞增殖受到显著抑制,且较VD组和VD-C组细胞增殖明显减少,其差别有统计学意义。
NC及SC组大鼠CA1区、CA2和CA3区均未见BrdU阳性细胞,脑缺血后海马CA1和CA2区增殖细胞出现时间较晚,缺血后7d才有BrdU阳性表达,且数量较少。加用CIT后可使CA1区细胞增殖增加约1倍,CA2区细胞增殖提前到缺血3d开始出现且较高表达持续到术后21d。但联合应用WAY 100635后逆转了CIT增强的CA1和CA2区的细胞增殖。
VD组术后3d SVZ神经发生开始显著增强,加用CIT后神经发生的明显增强提前到术后1d。术后7d BrdU阳性表达至峰值(与术后3d组比较P<0.01),此后迅速下降(术后14d与7d比较差异显著,P<0.01),14d后下降趋势减缓。VD-C组各时相点BrdU表达情况与VD组比较无显著差异,而VD-CW组各时相点神经发生与VD-C组比较无显著差异。缺血后各实验组PCg和Str18区BrdU阳性表达增加。VD组术后1~3d皮层Ⅱ~Ⅵ层大脑皮质BrdU阳性表达开始增加,术后7d BrdU阳性表达较缺血3d明显增加(P<0.01),缺血14d增加更为显著(P<0.01),缺血21d BrdU阳性表达显著减少。VD-C组术后各时相点的皮层BrdU阳性表达较VD组明显增加(P<0.01),术后14d尤其显著。VD-CW组缺血各时相点BrdU阳性细胞数较VD组明显增加,但与VD-C组比较无显著差异。
2.各实验组大鼠脑内NSCs存活分化的情况:
脑缺血再灌注各实验组均可见双标记阳性细胞。①在海马DG,VD组新生细胞存活率较SC组显著下降,但双标记阳性细胞比率较SC组显著增高(P<0.05),其BrdU阳性细胞主要分化为Tuj-1阳性的不成熟神经元;CA1区BrdU阳性细胞主要表达Tuj-1和Calbindin-D28k标志物;BrdU/GFAP双标记阳性细胞散在分布于齿回GCL和海马门区。VD-C组新生细胞存活率成神经分化的比例增加,其海马DG和CA1区分化为Calbindin-D28k阳性成熟神经元的比例较VD组增加,但BrdU/GFAP双标记阳性率无明显改变。在VD-CW组则发现新生细胞存活和分化的比例显著降低,少见BrdU/Calbindin-D28k双标记阳性细胞。②皮层BrdU阳性细胞出现在PCg区、Str18区、PAC区等部位,以PCg区BrdU阳性表达最稳定。VD组BrdU阳性细胞存活率较SC组降低,但无统计学差异;VD-C组新生细胞存活率较VD组明显增高(P<0.05)。NS和SC组未发现双标记阳性细胞,VD组可见少量BrdU/Tuj-1和BrdU/Calbindin-D28k双阳性表达,较多BrdU阳性细胞表达GFAP。VD-C组BrdU/Tuj-1双阳性率与VD组比较无显著差异,但BrdU/Calbindin-D28k双阳性表达百分率较VD组显著升高(P<0.01),且细胞突起较长。虽然VD-CW组各项指标均较VD-C组降低,但差异无显著性。
3.海马5-HT1AR mRNA RT-PCR测定结果:
术后1d,各组5-HT1AR mRNA表达显著下调(P<0.01),术后3d开始回升,VD组海马5-HT1A受体mRNA表达在术后14d达到其峰值。和VD组比较,VD-C组除术后1d组外其余各组大鼠海马5-HT1A受体mRNA表达到丰度均显著升高(P <0.01),其表达峰值提前至术后7天,且一直到术后21d仍维持在相对较高水平。在CIT联合应用WAY100635的VD-CW组,5-HT1A受体mRNA的表达丰度从术后3d开始仍较VD组高,其中术后3d和7d亚组与VD组有显著差异;但VD-CW组术后各时相点5-HT1A受体mRNA的表达丰度均较VD-C组显著降低。
4.皮层和海马单胺类神经递质5-HT、DA和NE的HPLC检测结果
在海马:大鼠全脑缺血再灌注后7d 5-HT、DA和NE水平均降低,但其中NE水平的下降无统计学意义。VD组到术后21d海马单胺类神经递质水平接近正常。VD-C组大鼠海马5-HT水平升高近1倍(P <0.01),DA和NE水平无明显变化。VD-CW组5-HT水平虽较VD-C组有升高但无显著差异,DA和NE水平亦无显著变化。在皮层:大鼠全脑缺血再灌注后7d 5-HT水平下降,但DA和NE水平无明显变化,术后21d时均接近正常水平。VD-C组5-HT和NE水平与VD组比较无显著变化,但DA水平则较VD组明显升高(P <0.05)。VD-CW组皮层5-HT水平上升明显(约为SC的3倍),皮层DA水平较VD-C组明显下降(P <0.01),而NE水平无明显变化。
5.海马CA1区神经元存活情况:
各实验组大鼠海马CA1区神经元均较SC组显著减少,且均在术后7d程度最严重,此后海马CA1区神经元数量开始逐渐恢复。其中,VD-C组恢复的趋势较VD组明显,而VD-CW组的恢复趋势最为缓慢。各实验组海马CA1区神经元减少的程度不同:和VD组比较,VD-C组术后各时相点CA1区神经元均较多,且差异显著(P <0.01);而VD-CW组的CA1区神经元数量却较少,除了7d和14d组差异显著性在P <0.05外,其余各时相点的差异均非常显著(P <0.01)。
6.大鼠Moris水迷宫行为学检测结果:
VD、VD-C和VD-CW组大鼠定位航行实验平均逃逸潜伏期(EL)在造模后均较NC及SC组显著延长(P<0.01),其后随时间推移逐渐缩短;但VD-C组EL延长程度较VD组减轻,且组术后14d、21d和42d的EL延长较VD组显著减少(P<0.05);相反,VD-CW组EL较VD组各14d、21d、42d亚组EL均显著延长。
VD、VD-C和VD-CW组大鼠空间搜索实验平台象限游泳距离百分比(DP)造模后均显著降低,但随时间推移逐渐上升;VD-C组DP均较VD组高(P <0.05),到术后42d已经与SC组物显著差异;相反,VD-CW组造模后各时相点DP均较VD组相应时相点明显减低(7d组P<0.05,14d、21d、42d亚组P<0.01)。大鼠穿越目标区的次数与DP的变化具有相同的趋势。
7.事件相关电位类P3检测结果:
各实验组除VD-C组术后42d亚组外,各时相点类P3L均较SC组显著延长。各实验组大鼠术后3d与术后1d亚组比较类P3L显著延长,术后7d类P3L进一步延长,其延长的程度在VD组和VD-C组无统计学意义,但在VD-CW组则显著延长。此后类P3L延长的程度随时间延长逐渐减轻,但减轻的程度不同:VD组和VD-CW组到术后42d类P3L才显著缩短;而在VD-C组,术后21d即较14d明显改善,术后42d的P3L较21d显著缩短且与SC组比较已经无显著差异。
研究结论:
1.全脑缺血再灌注可诱导成年大鼠脑内神经发生增强,以海马DG和SVZ区新生神经细胞的增殖最明显,海马CA1、CA2区和PCg皮层也发现脑缺血后神经发生增强的现象。海马和皮层增强的神经发生在术后14d达高峰,21d开始下降,一直可持续到术后42d;而SVZ神经发生的高峰出现在术后7d。大鼠脑缺血再灌注后水迷宫和类P3认知功能的改变,与海马及皮层BrdU阳性细胞的增殖没有相关性。
2. CIT可显著促进VD大鼠海马DG、CA1、CA2区和皮层的BrdU阳性细胞增殖,对SVZ区的新生神经细胞增殖无明显影响。同时,CIT可显著促进海马DG、CA1区和皮层新生神经细胞的成神经元分化,并且该作用与CIT改善VD大鼠认知障碍的效应关系密切。CIT的上述作用可被联合应用WAY100635所逆转。
3. CIT促进VD大鼠脑内神经发生的机制,可能与其提高中枢突触间隙5-HT水平、增加海马5-HT1A受体mRNA表达有关;而其改善动物认知障碍的作用,在术后21d内可能与其调节海马及皮层单胺类神经递质水平、保护海马CA1区神经元有关,在术后42d则可能是通过促进海马和皮层新生神经细胞的成神经元分化及神经保护作用实现的。
Vascular dementia (VD) is the second most common form of dementia after Alzheimer's dementia (AD) which seriously interfere the life of aged people. And till now, a restorative treatment has not been reached yet. VD is characterized by loss of neuronal cells especially in hippocampus, a region in the brain that has the ischemic injury vulnerability, and loss of executive function with milder memory loss. There is a growing body of evidence that neural stem cells(NSCs) reside in the adult central nervous system where neurogenesis occurs throughout lifespan. Neurogenesis concerns mainly two areas in the brain: the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ). Since the proliferation, differentiation, migration and integration of NSCs in hippocampus have close relationship with cognitive function, it provides a possible therapeutic strategy for ischemic injury repair. Although there have been consistent reports that cerebral ischemia increases the number of newly generated neurons that migrate from the SGZ into the granular cell layer(GCL) of DG and incorporate into functional synaptic circuitry in adult rats, but this still could not compensate the loss of neurons and the cognitive impairment. So it is becoming more and more important to find out a suitable microenvironment for further improve the neurogenesis triggered by ischemic injury. Fortunately, animal studies have shown strong neurogenetic function of serotonin and selective serotonin reuptake inhibitors (SSRIs) and the serotonin 1A receptor, which is abundant in hippocampus, has major effect during neurogenesis. However, it is yet not known whether SSRIs impact the proliferation and maturation of newborn neurons and the cognitive function of VD rats.
Here in this study, we test our hypothesis that citalopram(CIT), one of SSRIs, could promote neurogenesis and improve cognitive functions in vascular dementia model of rats and it’s action regulated by the function of serotonin 1A receptor. Our research could provide some experimental evidence for the mechanism of ischemic neurogenesis and choice for vascular dementia therapy.
Objective:
1. To interpret the characteristics of NSCs proliferation in vascular dementia model of adult rats.
2. To identify the influence of CIT on NSCs proliferation and differentiation in different region of the brain and on cognitive function of VD rats.
3. To elucidate the role of serotonin 1A receptor in ischemic neurogenesis and CIT effects in our vascular dementia model.
Methods:
1. Animals, drugs and establishment of rat model: Male Wistar rats (n=336) were randomly divided into five groups: normal control group(NC), sham operation control group(SC), transient cerebral ischemic group(VD), citalopram treated transient cerebral ischemic group(VD-C) and VD-CW group which treated with both citalopram and WAY100635. The later four groups were further divided into 1-, 3-, 7-, 14-, 21- and 42-days-post-operation subgroups. And in every subgroup 6 animals were involved. Citalopram(20mg/kg) and WAY 100635(0.3mg/kg) were injected intraperitoneally for 21 days before operation and the treatment proceeded until sacrifaction. BrdU(50mg/kg) was given for 7 days before sacrifaction for cell proliferation study. As for cell differentiation study, BrdU(50mg/kg) was given to 14-day-post-operation in VD, VD-C and VD-CW group, and rats were sacrificed 28 days after. The improved Pulsinelli’s 4-vessle occlusion was used to establish ischemia in rats.
2. Measurement for cognitive function: The water maze task was undertaken. Place navigation test and spatial probe test was to observe rats’spatial learning and memory abilities respectively. The escape latency (EL), distance percentage (DP) and times of passing through the platform were analyzed. And P3-like potential was observed too.
3. Observation for NSCs proliferation: Immunohistochemical-staining was preceded with freezing coronal brain slides of 35μm thick each. After sections were incubated in 0.3%TritonX-100 and 2mol/L HCl and results were shown by SABC-Cy3 or DAB. Sections were examined with an inverted microscope.
4. Observation for NSCs survival and differentiation: Double-label immunofluorescence staining was proceeded. After BrdU immunofluorescence staining, sections were incubated with Tuj1, Calbindin-D28k and GFAP respectively, to label immature, mature neurons and astrocytes, use different fluorescence coloration. And the resulting immunofluorescent signal was viewed under fluorescence microscope and confocal microscopy.
5. Nissl stain was proceeded to analyze the survival of CA1 neurons.
6. The expression of serotonin 1A receptor in hippocampus: After Isolation of total RNA and reverse transcription–PCR , Real-time PCR was preceded. Serotonin 1A receptor primers were 5'-GCCCCCCAAGAAGAGCCTGA-3' and 5'-GCCATCTTGCGCTTTGCTTC-3'. GAPDH was used as reference, and the primers were 5'-ACCACAGTCCATGCCATCAC-3' and 5'-TCCACCACCCTGTTGCTGTA-3'。
7. high-performance liquid chromatography(HPLC) was used to detect monoamine neurotransmitters in hippocampus.
8. Cell counting and statistical analysis: Cells were counted under high power (20×or 40×objective) on Olympus microscope with magnifying digital camera. Data analyzed by IPP 6.0 software. All the data are presented as the means±S.E.M. of the individual values for each rat in all groups. Statistical analysis of the data was performed using one-way ANOVA for multiple comparisons.
Results
1. The characteristics of NSCs proliferation in vascular dementia model of adult rats.
BrdU positive cells were observed mainly in dentate gyrus and SVZ and less expressed in cortex in normal rats.
In DG, BrdU-positive cells were gradually increased from 3 days after operation and reached its peak 14 days after operation with the cell number triple as much as that before ischemia. And the number of newly proliferated cells in VD-C group was twice as much as that in VD group from 3 days after ischemia. And in VD-CW group, the proliferation of NSCs was significantly decreased.
There was no BrdU-positive cells in CA1, CA2 and CA3 in normal rats. And NSCs cells were found in CA1 and CA2 7 days after operation, cell proliferated later and less than that in DG. By use of CIT, CA1 cell proliferation increased twice as that in VD group and CA2 cell proliferation was found 3 days after ischemia and continued 21 days after operation. But the cell proliferation was significantly down-regulated in VD-CW group compared with VD-C group.
In SVZ region, cell proliferation obviously up-graded from 3-day-after operation, and it was significantly further enhanced by use of CIT. In every experimental groups, number of BrdU-positive cells 7 days post-ischemia groups was significantly higher than that in 3 days post-ischemia groups(P<0.01). But after that, cell proliferation down-regulated rapidly with significant difference between 14 days to 7days post-ischemia(P<0.01). There was no obvious difference of BrdU-positive cell numbers between VD-C group and VD or VD-CW group.
Number of BrdU-positive cells began to rise in cortex PCg and Str18 area in all experimental groups after ischemia. In VD group, BrdU-positive cells emerged inⅡ~Ⅵlayer of cortex began to rise from 1~3 days post operation and obviously higher 7 days and 14 days after ischemia(P<0.01). Then the number significantly went down 21 days after operation. Number of BrdU-positive cells in VD-C group was much higher compared with VD group(P<0.01) and difference was most obvious 14 days after operation. In VD-CW group, BrdU-positive cells were higher than VD group but had no significant difference with VD-c group.
2. The survival and differentiation of newly generated cells:
Double labeled cells could be found in every experimental group after operation.①In DG, NSCs survival rate of VD group was lower than that in SC group but the percentage of double-labeled cell significantly higher(P<0.05). In group of VD, the BrdU-positive cells mainly differentiated into Tuj1-positive immature neurons in DG and into both immature and mature neurons with positive stain of Calbindin-D28k in CA1. And the BrdU-and-GFAP- positive cells scattered in GCL of DG and hilus. In VD-C group, newly generated cells in DG and CA1 differentiated into mature neurons obviously more than that in VD group and also had higher survival rate. And in VD-CW group, double positive of BrdU/Tuj1 and BrdU/Calbindin-D28k cell percentages were significantly decrease.②In the cortex, the BrdU-positive cells expressed relatively stable in PCg than in Str18 and PAC. NSCs’survival rate of VD group was lower than that in SC group with no significant difference. Survival rate of BrdU-positive cells in VD-C group was much higher than in VD group(P<0.05). Double-positive cell was not found in NS and SC groups but could be found in VD group of which had low percentage of BrdU/Tuj1 and BrdU/Calbindin-D28k staining and relatively high percentage of BrdU/GFAP staining. Compared with VD group, BrdU/Tuj1 double-staining percentage was similar but BrdU/Calbindin-D28k double-staining was much higher(P<0.01) in VD-C group. Although cell differentiation rate was lower in VD-CW group, there was no significant difference.
3. result of RT-PCR examination of serotonin 1A receptor mRNA
One day after transient cerebral ischemia, the relative expression level of serotonin 1A receptor mRNA dropped down obviously in VD, VD-C and VD-CW groups(p<0.01). It began to rise up from 3 days after ischemia. In VD group, the expression level reached its peak 14 days after operation. In, VD-C group, the relative expression levels of serotonin 1A receptor mRNA were much higher (P<0.01) except 1-day-post-ischemia and reached its peak 7 days earlier and continued keep its ascendancy to 21 days after ischemia compared with VD group. In VD-CW group, serotonin 1A receptor mRNA expression was higher than that in VD group from 3 days after operation with significant difference in 3- and 7-day post ischemia, but lower than that in VD-C group.
4. Level of monoamine neurotransmitters in hippocampus detected by HPLC
①In hippocampus: The level of serotonin(5-HT) dopamine(DA) and norepinephrine (NE) were dropped 7 days after cerebral ischemia with significant difference except NE. And the monoamine neurotransmitter returned normal 21 days post-ischemia in VD group. In VD-C group, the level of 5-HT rose twice as much as that in VD group(P<0.01) but the level of 5-HT in VD-CW group rose with no significant difference vs. VD-C group. The level of DA and NE didn’t change either in VD-C or VD-CW group.
②In cortex: The level of 5-HT dropped 7 days after cerebral ischemia with no change of NE and DA and returned normal 21 days post-ischemia. In VD-C group, the level of 5-HT and NE had no statistical difference but the DA level was significantly higher compared with that in VD group(P<0.05). In VD-CW group, the 5-HT level largely rose up, almost triple as much as that in SC group, the level of DA decrease obviously vs. VD-C group(P<0.01), and NE level didn’t change much.
5. Cell survival in CA1
The comparisons indicated that this effect was due to significantly lower cell densities in the ischemic animals as compared to sham-operated (p < 0.001). As compared to sham-operated animals, almost 90% of CA1 pyramidal cells showed signs of neuronal damage 7 days after operation and only regained nearly 65% of CA1 cell number 42 day post-ischemia. In contrast, CIT treated rats had 25% more CA1 neurons than non-treated ischemic rats. But this protective effect was blocked by co-administration of WAY 100635, a specific 5-HT1A receptor antagonist. These results provide evidence that CIT can induce a long lasting (i.e., 6 weeks) hippocampal protection against global cerebral ischemia. And this effect of CIT might be regulated by the function of 5-HT1A receptor.
6. cognitive function examined by Morris water maze test
Results from data analysis indicated that the average escape latency(EL) of all rats in every group was gradually decreased by the increase of trials in the place navigation tests. The EL in the three groups of VD,VD-C and VD-CW were significantly longer than that of the NC and SC groups(P<0.01). The group of VD-C existed longer escape latency(P<0.05), while the EL in this group of 14 days and 21 days after operation were significantly decreased compared with the VD group(P<0.05).In the contrast, after the administration of the WAY100635,he specific inhibitor of 5-HT1AR, the VD-CW rats showed significant longer escape latency.
To test the spatial memory ability, the spatial probe test was performed after the removal of the platform. The data showed that the DP spent in target quadrants had no difference between the NC and SC rats, and the DP of the VD,VD+C and VD+W were respectively decreased significantly. Furthermore, the administration of Citalopram made a better performance in memory compared with other groups(P<0.05) and almost returned to normal 42 days after ischemia. In contrast, the DP decreased sharply compared with VD-7d group(P<0.05) and VD-14, 21, 42d group(P<0.01). There was similar result of times of passing through the platform according to DP.
7. Observation of P3-like latency(P3L)
Except VD-C-42d group, the P3L prolonged significantly in all ischemic groups vs. SC group. The P3L extended largely 3 days than 1day and 7 days than 3 days after ischemia. These extensions had no statistic significance in VD and VD-C groups but really sharply prolonged in VD-CW group. After 7 days of ischemia, the degree of P3L extension extenuated as time goes on with differences in distinct groups. The significant decurtation of P3L did not emerge until 42 days after ischemia in both VD and VD-CW groups. But in VD-C group, the P3L ameliorated from 21 days post-operation and keep on improving to almost normal level 42 days post-operation.
Conclusions
1. Adult brain neurogenesis could be triggered by transient global ischemia. Three days after cerebral ischemia and reperfusion (CIR), enhanced neurogenesis emerged in hippocampus, cortex and SVZ with the most obviously enhancements in DG and SVZ. We found that neurogenesis in CA1, CA2 and PCg could be triggered by ischemia that had seldom been reported. The neurogenesis reached its peak 14 days after operation and decreased from 21-day-post-ischemia till 42 days after ischemia in hippocampus and cortex. And in SVZ, neurogenesis reached its peak 7 days after operation. There was no correlation between changes of cognitive function evaluated by Morris water maze test and P3-like detection and proliferation of BrdU-positive cells in hippocampus and cortex.
2. Chronic administration of CIT (20mg/kg) could obviously enhance BrdU-positive cell proliferation in different brain region of VD rats, areas including DG, CA1, CA2 and cortex, but barely affected the proliferation of newly generated cells in SVZ. Meanwhile, newly generated cells in DG, CA1 and cortex differentiated more into neurons by treatment of CIT and it had close relationship with the curative facts of CIT on cognitive impairments of VD rats. The effects of CIT mentioned above could be reversed by co administration with WAY 100635.
3. The mechanism of neurogenetic effect of CIT in VD rats might be concerned with its function of elevating the 5-HT level in synaptic space in the central nervous system (CNS) and/or of promoting the expression of 5-HT1A receptor mRNA. CIT could ameliorate the cognitive impairment via modulate the CNS levels of monoamine neurotransmitters within 21 days after operation and via neuroprotective effect or promote hippocampus and cortex newly generated cells differentiate into neurons 42 days after ischemia.
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