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1.
帕金森病大鼠黑质细胞凋亡与左旋多巴剂量的关系   总被引:9,自引:3,他引:6  
目的 研究左旋多巴对黑质细胞的神经毒性作用,探讨左旋多巴治疗帕金森病(PD)的最佳方案。方法 选用Wistar大鼠,采用改良的Thomas方法,用6-OHDA行脑立体定向注射术制作大鼠帕金森病(PD)模型100只,随机分为两大组:PD模型组(n=25)、L-dopa治疗组(n=75),采用TUNEI。方法 观察左旋多巴小、中、大3种不同剂量[10,50,100mg/(k&;#183;d)]、不同的作用时间(1,3,5,7d)对帕金森病大鼠黑质细胞的毒性作用,并观察治疗后7d各项指标的变化。结果 同一时点PD大鼠黑质细胞凋亡数随着左旋多巴治疗的时间、剂量增加而增加;1~7d小剂量组:从(412&;#177;35)个/mm^2减少到(403&;#177;22)个/mm^2,中剂量组从(468&;#177;33)个/mm^2增加到(605&;#177;37)个/mm^2.大剂量组从(759&;#177;61)个/mm^2减少到(486&;#177;37)个/mm^2;7~14d各时点减少。结论 左旋多巴能加速PD大鼠黑质细胞凋亡,小剂量、间隔使用左旋多巴能有效减少其神经毒性作用。  相似文献   

2.
帕金森病大鼠黑质细胞凋亡与左旋多巴剂量的关系   总被引:1,自引:0,他引:1  
目的研究左旋多巴对黑质细胞的神经毒性作用,探讨左旋多巴治疗帕金森病(PD)的最佳方案。方法选用Wistar大鼠,采用改良的Thomas方法,用6-OHDA行脑立体定向注射术制作大鼠帕金森病(PD)模型100只,随机分为两大组:PD模型组(n=25)、L-dopa治疗组(n=75),采用TUNEL方法观察左旋多巴小、中、大3种不同剂量犤10,50,100mg/(kg·d)犦、不同的作用时间(1,3,5,7d)对帕金森病大鼠黑质细胞的毒性作用,并观察治疗后7d各项指标的变化。结果同一时点PD大鼠黑质细胞凋亡数随着左旋多巴治疗的时间、剂量增加而增加;1~7d小剂量组:从(412±35)个/mm2减少到(403±22)个/mm2,中剂量组从(468±33)个/mm2增加到(605±37)个/mm2,大剂量组从(759±61)个/mm2减少到(486±37)个/mm2;7~14d各时点减少。结论左旋多巴能加速PD大鼠黑质细胞凋亡,小剂量、间隔使用左旋多巴能有效减少其神经毒性作用。  相似文献   

3.
6-羟基多巴胺诱发大鼠黑质细胞凋亡的实验研究   总被引:3,自引:1,他引:2  
目的:为了解证实细胞凋亡参与了帕金森病(Parkinson disease,PD)的发病和黑质细胞凋亡的调控因素。方法:通过脑立体定位注射6-羟基多巴胺(6-OHDA)建立大鼠PD模型。采用TUNEL法、原位杂交技术、电镜观察等,选择6-DHDA注射术后1、3、5、7、14及21d为研究时点,观察大鼠PD模型形成过程中黑质细胞凋亡的数量及超微结构变化情况,并检测黑质细胞Bcl-2 mRNA、P53 mRNA表达情况及铁的浓度。结果:用TUNEL法发现黑质细胞存在细胞凋亡,与对照组比较差异有显著性(P<0.05),7d 细胞凋亡数为最高,21d最低;电镜观察在此过程中黑质细胞存在典型的细胞凋良,并逐渐加重;Bcl-2和铁随时间增加而升高,P53则在1d为最高,其后很快下降,但都高于对照组(P<0.05)。结论:6-OHDA能诱发大鼠黑质细胞凋亡,细胞凋亡参与了PD发病,并受到Bcl-2、P53和铁的影响。  相似文献   

4.
曹非  孙圣刚  童萼塘  骆芳 《中国康复》2007,22(5):298-299
目的:观察6-羟基多巴胺(6-OHDA)能否诱发黑质细胞凋亡以及Bax蛋白表达与黑质细胞凋亡的关系。方法:72只Wistar雄性大鼠随机分为对照组36只及通过脑立体定位注射60HDA的方法建立的大鼠帕金森病模型组(PD)组36只,采用TUNEL方法、免疫组织化学、电镜等观察术后l、7、14及21d时2组大鼠脑黑质细胞凋亡的数量及超微结构变化,并检测黑质细胞Bax蛋白的表达。结果:术后TUNEI.法发现,与对照组比较,PD组存在明显的黑质细胞凋亡(P%0.05),且在1—21d时细胞凋亡数逐渐增高;电镜观察显示,PD组黑质细胞存在典型细胞凋亡,Bax蛋白表达在ld为最高,其后很快下降,但仍显著高于对照组。结论:6-羟基多巴胺能诱发大鼠黑质细胞凋亡,Bax蛋白是黑质细胞凋亡的关键启动因素。  相似文献   

5.
电针治疗对帕金森病大鼠多巴胺能神经元的影响   总被引:1,自引:0,他引:1       下载免费PDF全文
目的 观察电针治疗对帕金森病大鼠黑质多巴胺(DA)能神经元的影响。方法 选取Wistar大白鼠40只,随机分为正常组、假手术组、模型组和电针组,以6-羟基多巴胺(6-OHDA)注入中脑右侧黑质制作单侧黑质损毁的帕金森病大鼠模型,电针组采用电针进行治疗。检测各组大鼠黑质酪胺酸羟化酶(TH)阳性神经元数、DA能神经元凋亡数及纹状体DA含量。结果 与正常组和假手术组比较,模型组大鼠损毁侧DA能神经元凋亡数增加,TH阳性神经元数和纹状体DA含量减少,差异均有统计学意义(均P〈0.05);与模型组比较,电针组大鼠损毁侧DA能神经元凋亡数减少,TH阳性神经元数和纹状体DA含量增加,差异均有统计学意义(均P〈0.05)。结论 电针治疗对帕金森病黑质DA能神经元损伤有一定的防治作用。  相似文献   

6.
6—羟基多巴胺诱发大鼠帕金森病的实验研究   总被引:2,自引:0,他引:2  
目的:研究自由基,神经营养因子及细胞凋亡在帕金森病发病中的变化。方法:通过脑立体定向注射6-羟基多巴胺的方法建立大鼠PD模型,采用TUNEL法。免疫组化技术,生化方法。观察大鼠黑质细胞凋亡数量,方状体多巴胺含量,脑胶质源性神经营养因子(GDNF)表达及自由基和在酶的变化。结果:PD大鼠黑质存在明显的细胞凋亡,自由基反应增强,抗自由基酶和胶纹状体多巴胺含量及GDNF减少,与对照组存在显著性差异(P<0.05)。结论:自由基反应增强,营养因子缺乏及细胞凋亡参与了PD的发病,可能是其发病机制之一。  相似文献   

7.
细胞凋亡在帕金森病发病机制中的作用   总被引:5,自引:0,他引:5  
目的:研究帕金森病(PD)病因中细胞凋的发生及作用机制。方法:应用6-OHDA毁损大鼠纹状体,以制备PD大鼠模型,应用酪氨酸羟化酶(TH)和DNA原位末端标记免疫组化双标染色检测黑质内多巴胺(DA)神经元细胞凋亡的发生及其变化规模。结果:成功复制出符合临床特点的PD大鼠模型,其黑质内DA神经元的丢失是以细胞凋亡为主要形式,且于术后2周及1月为最明显,术后2个月仍然存在细胞凋亡情况,结论:黑质内DA神经元细胞凋亡的发生将使其数目减少,从而导致帕金森病的发生其机制可能与纹状体区病变有关。  相似文献   

8.
背景:帕金森病治疗的经典药物是左旋多巴,但是长期应用会产生异动症等并发症。 目的:观察左旋多巴对帕金森病模型大鼠学习记忆能力的影响,并探讨其机制。 方法:应用6-羟多巴胺制作帕金森病大鼠模型。将228只造模成功的帕金森病大鼠分为对照组和实验组,实验组大鼠分别按10,20,30 mg/(kg?d)腹腔注射左旋多巴,连续28 d,然后分别于腹腔注射后1,3,5,7,14,28 d测定其学习记忆能力及血浆同型半胱氨酸和叶酸水平。测定大鼠海马区乙酰胆碱酯酶活性,并应用Bielschowsky染色观察海马神经原纤维缠结。 结果与结论:随左旋多巴剂量增大、应用时间延长,可明显降低大鼠学习记忆能力(P 〈0.001);升高血浆同型半胱氨酸水平,降低叶酸水平(P 〈0.001);降低大鼠海马区乙酰胆碱酯酶活性(P 〈0.001);增多大鼠海马区神经原纤维缠结(P=0.000)。提示大量使用左旋多巴可造成帕金森病模型大鼠学习记忆能力明显下降,引起海马区乙酰胆碱酯酶活性下降,促进海马区神经原纤维缠结增多,其机制可能与升高同型半胱氨酸有关。  相似文献   

9.
脂多糖诱发大鼠黑质多巴胺能神经元变性   总被引:1,自引:0,他引:1  
目的:观察脂多糖(Lipopo1ysaccharide,LPS)对黑质多巴胺(DA)能神经元的毒性作用,探讨帕金森病(PD)发病机制。方法:脑立体定位注射LPS入大鼠脑黑质后,采用酪氨酸羟化酶(Tyrosine hydroxylase,TH)免疫组织化学染色,观察不同剂量LPS和5μgLPS注射后不同时间点黑质DA能神经元的损伤状况。结果:0.1—10μgLPS注射后14d,导致TH^ 细胞数下降分别为5%、15%、20%、45%、96%和99%;5μgLPS注射后与对照组相比,TH^ 细胞数3d后开始下降,14d明显减少,仅为5%,30d后基本消失。结论:LPS能诱导黑质DA能神经元变性.呈剂量和时间依赖性。  相似文献   

10.
目的:帕金森病最终都表现为患者中脑黑质多巴胺能神经元缺失,观察帕金森病发病过程中黑质神经元的缺失形式。方法:实验于2003-05/12在北京市神经外科研究所完成。取SD大鼠25只,按随机数字表法分为2组:①帕金森病模型组大鼠(n=21)立体定向下于右侧内侧前脑束区注射6-羟多巴(2g/L),术后皮下注射阿扑吗啡05mg/kg诱导旋转行为,大于7r/min视为成功偏侧帕金森病大鼠模型。②对照组大鼠(n=4)注射等剂量含0.2g/L抗坏血酸的生理盐水。分别于术后7d,2周、4周随机抽取帕金森病模型组大鼠(n=7)处死,取中脑组织切片进行Nissl染色,检测切片黑质致密区灰度值;应用DNA原位末端标记技术检测凋亡细胞,并与对照组对比。结果:死亡大鼠作随机补充,进入结果分析仍为25只大鼠。①实验成功复制出21只符合临床特点的帕金森病大鼠模型,多数大鼠于术后一两周出现旋转行为,2周时达到高峰,显著高于术后3,7d[(13.83±2.69,2.67±1.00,9.33±4.07)r/min(P<0.05)]。②术后7d,2周、4周模型组大鼠损毁侧黑质致密区的灰度值分别为149.50±13.14,117.29±10.62,110.41±17.34,均显著低于对照组(169.56±7.13)(P<0.05),模型2周组显著低于模型7d组(P<0.05)。③模型组大鼠术后2周的凋亡细胞最多,显著高于术后7d和4周组(3.60±0.27,3.07±0.39,2.27±0.43,P<0.05)。对照组未见到明显凋亡细胞。结论:6-羟多巴诱导的帕金森病大鼠损毁侧中脑组织黑质致密区中存在多巴胺能神经元凋亡,细胞凋亡在帕金森发病中可能起关键作用。  相似文献   

11.
Levodopa dose and severity of Parkinson's disease (PD) are recognized risk factors for levodopa-induced dyskinesia (LID) in humans. The purpose of the present study was to evaluate the ability of these variables to predict severity of LID in a rat model of PD. Varied concentrations of 6-hydroxy-dopamine were injected into the midbrain to produce wide ranges of dopamine depletion in striatum. Three weeks later, rats were given daily injections of levodopa (2-10 mg/kg i.p.) plus benserazide (12.5 mg/kg i.p.) for 15 days. Abnormal involuntary movements (AIMs) were measured for limb, axial, orolingual, and rotatory movements. Dose-response analysis for total AIM scores yielded a levodopa ED50 value of 3.2 mg/kg on treatment day 15. There were strong interrelated correlations between individual AIM categories (rho > 0.7) and for each AIM category in regard to total AIM score (rho > 0.7). In rats that received levodopa doses that were greater than the ED50, rates of amphetamine-induced rotation were significantly correlated with total AIM scores (rho = 0.413). However, of those rotating >5 times/min, 34% had relatively low AIM scores (<8). Likewise, there was a significant correlation between percentages of tyrosine hydroxylase (TH) loss and total AIM scores (rho = 0.388). However, in those rats that had >85% TH loss, 30% had AIM scores <8. Our results show that given an adequate dose and magnitude of striatal dopamine depletion, levodopa produces dyskinesia with a continuous spectrum of severity. Although levodopa dose and level of dopamine depletion are significant risk factors for LID, we conclude that other factors must contribute to LID susceptibility.  相似文献   

12.
Levodopa is the "gold standard" for the symptomatic treatment of Parkinson's disease (PD). There is a theoretical concern, however, that levodopa might accelerate the rate of nigral degeneration, because it undergoes oxidative metabolism and is toxic to cultured dopaminergic neurons. Most in vivo studies do not show evidence of levodopa toxicity; levodopa is not toxic to normal rodents, nonhuman primates, or humans and is not toxic to dopamine neurons in dopamine-lesioned rodents or nonhuman primates in most studies. However, the potential for levodopa to be toxic in vivo has not been tested under conditions of oxidative stress such as exist in PD. To assess whether levodopa is toxic under these circumstances, we have examined the effects of levodopa on dopamine neurons in mesencephalic cultures and rat pups in which glutathione synthesis has been inhibited by L-buthionine sulfoximine. Levodopa toxicity to cultured dopaminergic neurons was enhanced by glutathione depletion and diminished by antioxidants. In contrast, treatment of neonatal rats with levodopa, administered either alone or in combination with glutathione depletion, did not cause damage to the dopamine neurons of the substantia nigra or changes in striatal levels of dopamine and its metabolites. This study provides further evidence to support the notion that although levodopa can be toxic to dopamine neurons in vitro, it is not likely to be toxic to dopamine neurons in vivo and specifically in conditions such as PD.  相似文献   

13.
目的:探讨1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导小鼠多巴胺能神经元凋亡的规律以及尼古丁对其的保护作用。方法:取28只小鼠(PD组)腹腔注射MPTP 30 mg/(kg·d),共7 d,建立小鼠帕金森病模型;取4只小鼠(Nic组)腹腔注射尼古丁(2 mg/kg,每天5次,共17 d);取4只小鼠(Nic+MPTP组)给予尼古丁预处理和MPTP;取4只小鼠(对照组)仅给予等量生理盐水。应用酪氨酸羟化酶(TH)免疫组织化学染色和TUNEL染色,观察各组黑质多巴胺能神经元数目改变和凋亡细胞的变化规律。结果:慢性MPTP处理过程中,小鼠黑质TH阳性细胞数逐渐减少,于MPTP注射第3天开始出现TUNEL阳性细胞,并于第8天达到高峰。与PD组相比,Nic+MPTP组TH阳性细胞丢失和TUNEL阳性细胞增多的程度显著降低(P<0.05)。结论:采用慢性MPTP处理的模式,可诱导小鼠黑质多巴胺能神经元凋亡;尼古丁对这类神经元具有明显保护作用。  相似文献   

14.
目的 :研究自由基、神经营养因子及细胞凋亡在帕金森病发病中的变化。方法 :通过脑立体定向注射 6 羟基多巴胺的方法建立大鼠PD模型 ,采用TUNEL法 ,免疫组化技术 ,生化方法 ,观察大鼠黑质细胞凋亡数量 ,纹状体多巴胺含量 ,脑胶质源性神经营养因子 (GDNF)表达及自由基和抗自由基酶的变化。结果 :PD大鼠黑质存在明显的细胞凋亡 ,自由基反应增强 ,抗自由基酶和纹状体多巴胺含量及GDNF减少 ,与对照组存在显著性差异 ( P <0 0 5 )。结论 :自由基反应增强 ,营养因子缺乏及细胞凋亡参与了PD的发病 ,可能是其发病机制之一  相似文献   

15.
Prompted by conflicting reports of both agonist and antagonist properties of the S-(+)-enantiomer of the potent dopamine agonist R-(-)-N-n-propylnorapomorphine (NPA), we carried out extracellular, single unit recording studies to compare the effects of both enantiomers on substantia nigra and ventral tegmental area (VTA) dopamine neurons in male rats anesthetized with chloral hydrate. Like the classic dopamine agonist apomorphine, R-(-)-NPA inhibited cell firing in both populations. Mean cumulative doses to inhibit firing by 50% (ID50) were 0.53 micrograms/kg for nigral and 0.50 micrograms/kg for VTA dopamine cells, respectively, reflecting a potency for R-(-)-NPA 10-fold greater than that of apomorphine for inhibition of nigral dopamine cells (ID50 5.3 micrograms/kg). Inhibitions elicited by R-(-)-NPA could be fully reversed by i.v. haloperidol (0.2 mg/kg) but not by S-(+)-NPA in doses up to 0.9 mg/kg. Interestingly, S-(+)-NPA also exhibited agonist activity in both cell groups but with a much lower potency than R-(-)-NPA. In addition, VTA dopamine cells displayed a significantly greater sensitivity to the drug: ID50 values of 149 micrograms/kg vs. 514 micrograms/kg for VTA and substantia nigra neurons, respectively (P less than .01). Prior administration of haloperidol (0.1 mg/kg) consistently and fully prevented the inhibitory effects of S-(+)-NPA on all cells tested, although subsequent administration of haloperidol (up to 1.6 mg/kg) did not reverse completely S-(+)-NPA-induced inhibitions in all cases.(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   

16.
Parkinson's disease (PD) is characterized by the degeneration of nigrostriatal dopaminergic neurons. Its primary clinical symptoms are akinesia, tremor, and rigidity, which usually start from one side, resembling the lateralization in hemiparkinsonian rats having 6-hydroxydopamine-induced unilateral lesion of the medial forebrain bundle. A novel exploratory Y-maze was designed to detect the lateralization of hemiparkinsonian rats in terms of biased turns in the maze. Dopamine agonists levodopa (L-3,4-dihydroxyphenylalanine, 10-30 mg/kg) and apomorphine (0.1-0.3 mg/kg), but not methamphetamine (0.5-2 mg/kg), improved the lateralization in the rat model. However, high doses of the dopamine agonists, 30 and 0.3 mg/kg, respectively, caused small movements in the arms that seemed to parallel the increase in counts per turn in the Y-maze. Interestingly, the muscarinic antagonists trihexyphenidyl and scopolamine improved lateralization moderately, while increasing total turns, an index of locomotive activity. (-)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) (0.3 mg/kg), an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, increased total counts, but did not alleviate the lateralization. The alpha2-adrenoceptor antagonist idazoxan (1 and 10 mg/kg) and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (1 and 3 mg/kg), a non-NMDA glutamate receptor antagonist, did not affect any of the indices. These findings suggest that the clinical action of drugs on unbalanced movement in PD could be predicted by measuring their effects on lateralization of the 6-hydroxydopamine-lesioned rat model in this exploratory Y-maze.  相似文献   

17.
3-硝基丙酸预处理阻止黑质多巴胺神经元细胞凋亡   总被引:2,自引:0,他引:2  
目的:观察3 硝基丙酸(3 NP)预处理时黑质多巴胺(DA)神经元细胞凋亡改变的作用机制及5 羟癸 酸(5 HD)对3 NP效果的影响。方法:25只雄性SD大鼠随机分为5组各5只。右侧黑质内立体定向注射6 羟多 巴胺(6 OHDA)建立帕金森病(PD)模型组,对照组大鼠立体定向和腹腔注射生理盐水,3 NP组在对照组的基础上 腹腔注射3 NP(20mg/kg),预处理组(CPC组)造模前24h给予3 NP(20mg/kg),5 HD组于造模前10min侧脑 室内给予5 HD(5mg/kg)。采用缺口末端标记原位检测法及免疫组化法检测黑质DA神经元细胞凋亡率及酪氨 酸羟化酶(TH)阳性细胞数。结果:PD组、CPC组及5 HD组与对照组和3 NP组比较细胞凋亡率均明显增高,损 毁侧TH阳性细胞数显著降低(P<0.01或P<0.05);CPC组与PD组比较细胞凋亡率降低,TH阳性细胞数增多 (P<0.05);5 HD组与PD组比较则差异无显著性意义(P>0.05)。结论:3 NP预处理可抑制细胞凋亡,而5 HD 可阻断3 NP预处理保护效应。线粒体ATP敏感性钾通道激活参与3 NP预处理神经元保护作用。  相似文献   

18.
目的探讨应用灯盏花素减轻顺铂对大鼠肾损害及肾细胞凋亡的作用机制。方法48只SD大鼠分为对照组、模型组、25mg/kg灯盏花素组(灯盏花素1组)和50mg/kg灯盏花素组(灯盏花素2组)各12只。对照组给予羧甲基纤维素钠溶液灌胃,模型组、灯盏花素1组和2组均腹腔注射顺铂8mg/kg造模。灯盏花素1组和2组分别以25mg/kg和50mg/kg灯盏花素灌胃,给药7d后计算4组肾脏指数,采用原位缺15末端标记法检测肾细胞凋亡情况,左肾采用蛋白质印迹法检测肾皮质Bax、Bcl-2表达水平,右肾采用免疫组织化学法检测肾组织凋亡蛋白Bax和Bcl-2表达水平。结果模型组、灯盏花素1组和2组肾脏指数、凋亡指数及Bax、Bcl-2表达水平高于对照组(P〈0.05);灯盏花素2组肾脏指数、凋亡指数、Bax表达水平及Bax/Bcl-2比值低于模型组、Bcl-2表达水平高于模型组(P〈0.05);灯盏花素1组肾脏指数和凋亡指数高于2组(P〈0.05)。结论灯盏花素可增强凋亡蛋白Bcl-2表达、降低Bax表达,影响线粒体凋亡通路,从而减轻顺铂对肾损害大鼠肾细胞的凋亡。  相似文献   

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