摘要
2-(α-羟基戊基)苯甲酸钾盐(Potassium 2-(1-hydroxypentyl)-benzoate,d1-PHPB)是本所设计合成的新化合物,它是丁基苯酞(3-n-butylphthalide,d1-NBP)的前药。d1-NBP是一类抗缺血性脑卒中新药,对缺血脑组织具有多种神经保护作用。推测,d1-NBP可能通过神经保护作用对老年痴呆有治疗作用。但是,d1-NBP在开发过程中存在一些缺点。d1-PHPB是针对它的缺点设计合成的丁基苯酞内酯环开环的产物,具有多方面的优点和创新点。本研究中,我们采用三种公认的老年痴呆模型观察了d1-PHPB对痴呆动物认知缺陷的改善作用,并探讨了其可能的作用机制。
1.d1-PHPB对脑低灌注大鼠学习记忆障碍的影响及其机制
采用永久性结扎双侧颈总动脉的方法制备大鼠脑低灌注模型(2-VO大鼠),用Morris水迷宫检测d1-PHPB给药3周对动物近记忆和空间辨别力的影响。结果显示:d1-PHPB 39、129mg/kg、d1-NBP 100mg/kg和吡拉西坦600mg/kg可不同程度地缩短痴呆大鼠的潜伏期。d1-PHPB 39mg/kg组采取直线式、趋向式策略的次数明显多于溶剂对照组,其它各药各剂量组也有改善搜索策略的趋势。平台探索实验中,除d1-PHPB 129mg/kg和d1-NBP100mg/kg外,各给药组大鼠在目标象限的活动时间明显长于溶剂对照组,尤其d1-PHPB39mg/kg组。同时,d1-PHPB 39mg/kg组的第一次穿越目标时间显著短于溶剂对照组。表明,d1-PHPB可明显改善大鼠的学习记忆和探索行为,尤其中、大剂量。
生化测定结果显示:2-VO大鼠1个月后,海马ChAT活力下降趋势明显。d1-PHPB129mg/kg能显著提高海马ChAT活力,d1-PHPB 39mg/kg、吡拉西坦600mg/kg也有升高的趋势。
生化法测定抗氧化作用证明:d1-PHPB 13、39mg/kg、d1-NBP 100mg/kg和吡拉西坦600mg/kg可明显降低皮层SOD活力。除吡拉西坦外,各给药组有降低皮层CAT活力的趋势。GSH-Px活力在各组脑组织间没有明显差异。d1-PHPB三个剂量和d1-NBP 100mg/kg显著降低皮层MDA含量。各组间海马SOD活力和MDA含量没有明显差异。另外,生化测定还显示,各组之间脑组织ATP酶活力、LD和NO含量没有显著性差异。
用HE染色进行脑组织形态研究,结果显示,d1-PHPB三个剂量可不同程度地改善皮层和海马CA1、CA3区神经元形态异常,尤以39mg/kg作用显著。K-B染色发现,该药三个剂量对胼胝体和视束的病理改变也有不同程度的改善作用,其中39mg/kg作用最强。
用免疫组化方法对脑组织进行染色。在皮层,溶剂对照组GFAP阳性细胞数有增多的趋势,而各给药组该指标明显小于溶剂对照组,尤其d1-PHPB 39mg/kg组。在海马,各给药组的GFAP阳性细胞数明显小于溶剂对照组。在胼胝体,d1-PHPB 39mg/kg组该指标小于溶剂对照组。在视束,d1-PHPB 39、129mg/kg、d1-NBP 100mg/kg以及吡拉西坦600mg/kg组的GFAP阳性细胞数明显少于溶剂对照组。说明,d1-PHPB可明显减少2-VO大鼠脑组织活化的星形胶质细胞,尤其在海马和视束。
采用免疫组化法在皮层和海马CA1区证实,d1-PHPB 39mg/kg可明显增高K4P2的分布面积,该药13、129mg/kg及d1-NBP 100mg/kg则仅有增高的趋势。各药对皮层和海马MAP2的密度没有明显影响。
大鼠脑低灌注后BDNF免疫组化染色显示,在皮层和海马,各组间染色面积无明显差异。但从染色密度看,在皮层,d1-PHPB可增加BDNF的表达,其中39mg/kg作用最强;在海马,该药39mg/kg可增加其表达。
2.d1-PHPB对Aβ_((25-35))致大鼠痴呆后学习记忆的改善作用及其机制
侧脑室注射Aβ_((25-35))后第1天开始给药,连续两周,第9-13天进行水迷宫实验。结果显示:d1-PHPB 129mg/kg组的潜伏期明显短于溶剂对照组,39mg/kg组也有短于溶剂对照组的趋势。平台探索实验中,d1-PHPB 129mg/kg组目标象限活动时间百分比明显长于溶剂对照组,39mg/kg组也有长于溶剂对照组的趋势。另外,d1-PHPB有缩短动物第一次穿越平台时间的趋势。表明,大剂量d1-PHPB可明显改善大鼠的学习记忆能力。
抗氧化检测证明,d1-PHPB 39和129mg/kg可降低痴呆大鼠皮层SOD活力(大剂量有统计学意义)以及MDA含量,且有剂量依赖性。在海马,各组之间SOD活力和MDA含量无明显差异。
与乙酰胆碱合成、代谢相关的酶活力测定发现,溶剂对照组皮层ChAT活力未见明显改变,但与溶剂对照组比较,d1-PHPB 39mg/kg可显著增加ChAT活力,129mg/kg也有增加趋势。海马ChAT和AChE活力在各组之间无显著差异。
采用Western blotting方法检测磷酸化tau蛋白。结果显示:d1-PHPB可剂量依赖性地降低皮层396位点磷酸化tau蛋白的表达。在海马,模型组该蛋白表达增高趋势明显,但药物对其无明显影响。
3.d1-PHPB对快速老化小鼠学习记忆的改善作用及其机制
跳台实验发现,五月龄SAMP8的被动回避反应能力略有弱于SAMR1的趋势。而十和十五月龄SAMP8的被动回避反应能力均明显弱于同龄SAMR1。但十五月龄的减弱程度比十月龄未进一步增加。
水迷路实验观察错误次数和潜伏期两项指标,结果显示,五月龄SAMP8对台阶位置的记忆略弱于同龄SAMR1,十和十五月龄SAMP8的记忆能力明显弱于同龄SAMR1。随着月龄增加,两种小鼠的学习记忆能力逐步下降,十月龄后维持在低水平,十五月龄不再进一步降低。
以荧光强度降低值表示线粒体对Rhodamine123的摄取程度,间接反映线粒体膜电位。三个月龄实验中,SAMP8的荧光强度降低值均明显低于SAMR1,其中十五月龄差异最大。从五到十月龄,两种小鼠的荧光强度降低值明显下降,十五月龄与十月龄相当。同时,皮层线粒体ATP酶活力,SAMP8和SAMR1从五到十月龄降低明显,而十五同十月龄比较则变化较小。各月龄SAMP8均显著低于同龄SAMR1。
生化研究显示:五和十月龄时,两种小鼠脑组织ChAT活力均维持在较高水平,而十五月龄时均显著下降。十月龄时SAMP8海马的ChAT活力低于同龄SAMR1。说明ChAT活力在不同月龄两种动物脑组织间差异较小。皮层AChE活力在各月龄两种小鼠间无显著差异。但在海马,五、十月龄SAMP8的AChE活力显著高于同龄SAMR1,十五月龄时,SAMP8却显著低于同龄SAMR1。
血清SOD随着月龄增加,无论在SAMP8还是SAMR1均逐渐减少。但十月龄SAMP8的SOD活力略微高于SAMR1。十五月龄SAMP8的SOD活力则显著低于SAMR1。血清MDA含量,随着月龄增加,在两种小鼠基本呈增加趋势,但十和十五月龄之间无明显差异。各月龄两种小鼠之间也无显著差异。
d1-PHPB对SAMP8小鼠作用的研究显示:10月龄SAMP8小鼠,连续给药35天。在跳台实验中,d1-PHPB 50和160mg/kg可剂量依赖性地减少SAMP8的电击次数,并延长电击潜伏期。水迷路实验发现,d1-PHPB可减少SAMP8进入盲端的错误次数,并缩短动物找到台阶的潜伏期。
同时,两个给药组海马SOD活力均明显下降。MDA含量降低趋势明显。在皮层,药物没有引起这两项指标的明显变化。d1-PHPB还可增高SAMP8海马ChAT活力,并有降低AChE活力的趋势。在皮层,该药没有影响二者的活力。另外,d1-PHPB 160mg/kg组皮层线粒体ATP酶活力高于对照组。
与对照组比较,d1-PHPB对海马396位点磷酸化tau蛋白的表达有显著的降低作用,并有一定的剂量依赖性。而对皮层该蛋白的表达没有明显影响。
以上结果表明,d1-PHPB对慢性脑低灌注和Aβ诱导的痴呆以及快速老化小鼠的认知缺陷均有确切的改善作用。除了改善大鼠脑组织的病理改变、减少活化的星形胶质细胞、增加微管相关蛋白2的分布和脑源性神经生长因子的含量外,在本研究中所涉及的三种痴呆动物模型,该药抗痴呆的主要机理为:增加ChAT活力而增加乙酰胆碱的合成、减轻氧化损伤以及减少脑组织中tau蛋白的过度磷酸化。总之,d1-PHPB可作用于慢性脑缺血和认知障碍的多个病理环节,是一个具有良好开发前景的抗痴呆药物。
Potassium 2-(1-hydroxypentyl)-benzoate(dl-PHPB) was a new compound synthesized by our institute,which is the prodrug of 3-n-butylphthalide(dl-NBP).dl-NBP is a first-class anti-ischemic stroke drug which had many nervous protective effects for ischemic brain tissue We deduced that it might have therapeutic action for senile dementia.But dl-PHPB has many advantages compared with dl-NBP.In this study,we adopted three dementia models to investigate the improvement of dl-PHPB on the cognitive deficits of dementia animals and observe its possible mechanisms.
PARTⅠEffects and mechanisms of dl-PHPB on the learning and memory deficits of cerebral hypoperfusion rats
In the present study,we administered drugs on day 10 to 30 after permanent occlusion of common carotid arteries(BCCAO) of rats.On the last six days,the behavioural test was performed,and then we determined some biochemical and immunohistochemical indexes in brains of dementia rats.The results are as follows:
dl-PHPB 39 and 129mg/kg,dl-NBP 100mg/kg and piracetam 600mg/kg reduced the latencies of dementia rats with different extent.Meanwhile,dl-PHPB 39mg/kg group used more linear and tendency modes than vehicle group.In the probe trial,except for dl-PHPB 129mg/kg and dl-NBP 100mg/kg,other groups spent more time in the target-quandrant than the vehicle,especially dl-PHPB 39mg/kg.In addition,the first crossing-platform time of dl-PHPB 39mg/kg group was significantly shorter than that of vehicle group.The above showed that dl-PHPB could significantly improve rats' cognition,especially large and middle doses.
We found that the ChAT activity in hippocampus had significant decreasing trend after BCCAO with biochemistry method,dl-PHPB 129mg/kg significantly increased the hippocampus ChAT activities of ischemic rats.
In cortex,the SOD activities of dl-PHPB 13 and 39mg/kg,dl-NBP 100mg/kg,and piracetam 600mg/kg were lower than that of vehicle group.Besides piracetam,other groups showed decrease trend on cortex CAT activity.The GSH-Px activity didn't show obvious differences among all groups,dl-PHPB and dl-NBP significantly decreased cortex MDA content.In hippocampus,cerebral ischemia and the drugs didn't affect SOD and MDA.In addition,there were no significant differences on ATPase activity,and LD and NO content among all groups.
HE-staining showed that three doses of dl-PHPB improved the abnormalities in cortex and hippocampus CA1 and CA3 with different extent,especially 39mg/kg.We also found that they had improvement on the pathological changes in corpus callosum and optic tract with K-B staining,especially 39mg/kg.
GFAP-positive astrocytes were investigated with immunohistochemistry method.In cortex, there was only a tendancy that GFAP-positive astrocytes in vehicle rats exceeded that of sham-operated rats,but all drugs could reduce astrocytes,especially dl-PHPB 39mg/kg.In hippocampus,all drugs also decreased the astrocytes,especially dl-PHPB 39 and 129mg/kg. In corpus callosum,GFAP-positive astrocytes in dl-PHPB 39mg/kg group were less than that of vehicle group.In optic tract,there were such results similar to that in hippocampus.
dl-PHPB 39mg/kg increased the MAP2 area in cortex and hippocampus CA1 region significantly.But the drugs didn't affect the MAP2 density.The BDNF areas in rats' brains of all groups had no significant differences.But dl-PHPB obviously increased the BDNF density in cortex,especially 39mg/kg,but in hippocampus,only dl-PHPB 39mg/kg increased it significantly.
PARTⅡImprovement and mechanisms of dl-PHPB on the cognitive deficits of dementia rats induced by Aβ_((25-35))
In this study,we adopted dementia rats induced by Aβ_((25-35)) through intracerebroventricular injection(i.c.v.).After administering for two weeks,rats' learning and memory was detected with Morris water maze.The related biochemical indexes and phospho-tau protein were examined to elucidate the action mechanisms of dl-PHPB.The results are as follows:
On day 9-13 after administration,water maze test was performed,dl-PHPB 39 and 129mg/kg dose-dependently reduced latency compared with the vehicle group.In the probe trial,dl-PHPB 129mg/kg group spent more time in the target-quandrant.In addition,the drug had a tendancy of reducing first crossing-platform time.These showed that large dose of dl-PHPB could significantly improve rats' learning and memory abilities.
dl-PHPB decreased the cortex SOD activity and MDA content dose-dependently.But in hippocampus,SOD activity and MDA content had no obvious differences among four groups.
dl-PHPB 39mg/kg increased the cortex ChAT activity compared with vehicle group. Meanwhile,dl-PHPB did not affect the cortex AChE activity and there were also no significant differences on hippocampus ChAT and AChE activity among all groups.
Meanwhile,we determined the phosphorylated tau protein of Ser396 site with Western blotting,dl-PHPB reduced dose-dependently tau protein expression in cortex.However,it did not significantly affect it in hippocampus.
PARTⅢImprovement and mechanisms of dl-PHPB on the cognitive deficits of senescence-accelerated mouse(SAM)
1.Comparative study on the learning and memory of different month-age SAM,and brain tissue biochemistry and morpholoy
We investigated the cognition,and brain biochemistry and morphology of five,ten,and fifteen-month-old SAMP8.In step-down test,there was a tendancy that the passive avoidance response ability of five-month-old SAMP8 was lower than that of same-age SAMR1.The abilities of ten and fifteen-month-old SAMP8 were significantly lower than that of same-age SAMR1.The difference on this between SAMP8 and SAMR1 increased gradually from five to ten-month age,but it did not increase from ten to fifteen-month age.
In water maze test,the spatial cognitive ability of five-month-old SAMP8 was slightly lower than that of same-age SAMR1,but the abilities of ten and fifteen-month-old SAMP8 were significantly lower than that of same-age SAMR1.We also found that their cognitive abilities decreased gradually from five to ten-month age and did not change obviously from ten to fifteen-month age.The difference on cognitive ability between them increased from five to ten-month age,but did not increase further from ten to fifteen-month age.
Decreasing value of fluorescence intensity was used to show mitochondria membrane potential indirectly.The values of three month-age SAMP8 were significantly less than that of same-age SAMR1.We also found that the mitochondria membrain potentials of SAMP8 and SAMR1 decreased gradually and their difference increased slightly with month-age increase.
Meanwhile,with the increase of month age,the mitochondria ATPase activity decreased gradually,but it did not decrease further after ten-month age.Moreover,the values of all month-age SAMP8 were significantly smaller than those of same-age SAMR1.
The brain ChAT activities of five and ten-month-old SAM were in high level,but it decreased obviously in fifteen-month-old.In addition,the hippocampus ChAT activity of ten-month-old SAMP8 was significantly lower than that of same-age SAMR1.In cortex,there were no differences on AChE activity between them.In hippocampus,the AChE activities of five and ten-month-old SAMP8 were significantly higher than that of same-age SAMR1.But the AChE activity of fifteen-month-old SAMP8 was lower than that of SAMR1.
With the increase of month age,the serum SOD activity of SAM decreased gradually.The SOD activity of ten-month-old SAMP8 was slightly higher than that of same-age SAMR1. However,in fifteen-month-old SAMP8,it was significantly lower than that of SAMR1.From five to ten-month age,the MDA level increased gradually,but there was no obvious difference between ten and fifteen-month age.Meanwhile,there was no significant difference between SAMP8 and SAMR1.
2.Improvement of dl-PHPB on the cognitive deficits of SAMP8
We administered two doses of dl-PHPB to ten-month-old SAMP8 for five weeks.On the last five days,we performed behavioral test to detect animals' cognitive abilities,and determined related biochemical indexes and phospho-tau protein of brain.
We found that dl-PHPB improved dose-dependently the passive avoidance response ability of SAMP8 in step-down test.Meanwhile,dl-PHPB reduced the number of entering non-exit and the latency of finding safe steps of SAMP8 in water maze trial.
Meanwhile,dl-PHPB reduced the hippocampus SOD activity of SAMP8 and had a strong tendency of decreasing the hippocampus MDA content.On the other hand,dl-PHPB increased dose-dependently the hippocampus ChAT activity and had a tendency of decreasing the hippocampus AChE activity.In addition,large dose of dl-PHPB had weak effect increasing the cortex mitochondria ATPase activity.
We determined the tau protein of one phosphorylation site(Ser396) with Western blotting. Compared with control,dl-PHPB decreased dose-dependently the expression of phospho-tau protein in the hippocampus of SAMP8,but it didn't affect it in cortex.
Taken together,we confirmed the therapeutic effects of dl-PHPB on VD,Aβ-induced dementia and the cognitive deficits in SAMP8.Meanwhile,these results indicated that such effects were mainly mediated by improving the pathologic changes,reducing active astrocytes, and increasing MAP2 and BDNF of VD rats' brains,alleviating the oxidative stress damage and enhangcing the cholinergic nerve function in brains of three animal models,and reducing the hyperphosphorylation tau protein in brain tissues of the later two animal models.In a word,dl-PHPB affected many pathologic courses of dementia and was a potentially beneficial and promising drug for the treatment of dementia.
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