丘脑底核脑深部电刺激治疗帕金森病的实验研究
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摘要
帕金森病(Parkinson’s disease, PD)是一种慢性退行性运动系统疾病,其主要的病理变化为黑质致密部多巴胺能神经元变性,纹状体内多巴胺(dopamine,DA)大量减少。丘脑底核(subthalamic nucleus ,STN) 脑深部电刺激(deep brain stimulation,DBS)对于中晚期帕金森病有良好的疗效,延长了运动障碍缓解期,手术安全性高,术后并发症较少,并且一部分病人术后可逐渐减少口服左旋多巴类药物的剂量。但DBS STN仍是一项有待于探索的领域,许多问题仍待解决,包括一些基本理论如作用机理、长期疗效的评定以及临床适应征等。
PD的病理学改变主要是黑质纹状体系统DA的减少伴有基底节神经核团的功能改变。多巴胺神经递质在PD的病程及治疗中起到了重要的作用。目前有研究表明,刺激鼠PD模型的STN核,可以增加纹状体区DA的释放和代谢。但是也有学者通过对临床病例的研究后提出,STN DBS治疗后并不能增加纹状体区DA的释放。因为6-羟基多巴(6-hydroxy-dopamine,6-OHDA)制备的鼠PD模型和人PD差别较大,并且动物试验研究所用的高频电刺激均为短期结果,临床病例研究有很多方面受到了限制。因此,本研究采用目前与人类PD最接近的MPTP灵长类动物模型,对猴PD模型STN核给予长期慢性高频电刺激,观察纹状体区域DA系统的变化,并结合了临床PD病人STN DBS手术前后的影像学资料进行对比研究,以确定STN DBS治疗后纹状体多巴胺神经递质的代谢变化,对STN核脑深部电刺激的作用机理和可能的神经保护机制作出合理的分析,为临床提高治疗帕金森病疗效,探索一种有效的方法延缓或阻止帕金森病的病程提供理论基础。
第一部分:偏侧猴帕金森病模型的制作
目的:分别采用血管内介入和手术两种方法颈内动脉注射1-甲基-4-苯基-1,2,3,6四氢吡啶(1-methy-4-phenyl-1,2,3,6-tetrahydropy-rindine,MPTP)制备偏侧猴PD模型,为下一步STN DBS实验提供帕金森病灵长类动物模型,并对两种制
备模型的方法进行比较。
材料和方法:动物均采用老年健康恒河猴,年龄均在10岁龄以上,体重在5～7Kg。制备模型药物采用MPTP。方法有以下二种:
血管内介入方法:恒河猴2只,全麻后在数字减影血管造影(digital subtraction angiography,DSA)下, Seldinger法股动脉穿刺,置5F鞘,4F单弯造影管超选颈内动脉造影,确认造影管置入颈内动脉后,缓慢注入MPTP生理盐水溶液(0.2mg/ml)。
直接手术方法:恒河猴2只,全麻后切开一侧颈部皮肤,经钝性分离暴露一侧颈总动脉,向上继续分离,显露颈动脉分叉部,暂时夹闭颈外动脉,缓慢注入MPTP生理盐水溶液(0.2mg/ml)。
术后均进行行为学观察和评估,指标包括运动障碍评分,阿朴吗啡诱发旋转实验等。MRI影像学检查验证注药侧黑质及纹状体区域信号强度变化,单光子放射计算机断层显像术 (single photon emission computed tomography, SPECT)对多巴胺转运体(Dopamine Transporter, DAT)及多巴胺D2受体(D2R)进行检查,与正常侧对比观察MPTP对于纹状体区多巴胺神经递质系统的损伤情况。待模型稳定后6个月,猴处死分别取两侧尾核、壳核和黑质组织,行病理切片,HE 和酪氨酸羟化酶(tyrosine hydroxylase ,TH)免疫组织化学染色。猴制作模型前后的脑脊液(cerebrospinal fluid,CSF)标本中的DA及其代谢产物的高效液相色谱-电化学法(high performance liquid chromatography and electrochemical detection , HPLC-ECD)检测。
结果:两种不同的方法制备偏侧PD模型后,行为学观察均发现猴自主运动明显减少,注药对侧肢体肌张力增高,部分猴伴有静止性震颤,运动迟缓,向患侧趴伏,步态不稳,运动障碍评分1个月后稳定在6分以上。阿朴吗啡 (apomorphine, APO)试验可诱发出特殊的向健侧的旋转动作。 MRI检查显示注药侧纹状体区域信号较对侧稍减低,未观察到注药侧黑质区域的信号改变。SPECT检查显示注药侧纹状体区的DAT明显降低,并一直保持较低状态,多巴胺D2受体在一个月时注药侧较正常侧摄取浓度明显增高, 3个月后仍保持稳定。
HPLC-ECD检测CSF中DA及其代谢产物二羟苯乙酸(dihydroxyphenylacetic acid ,DOPAC)和高香草酸(homovanillic acid ,HVA)含量发现给予MPTP1周后迅速下降,平均下降98%以上,并且一直保持在较低的水平。病理切片经HE 染色和TH免疫组织化学染色,发现注药侧黑质区域神经细胞变性减少,纹状体区域的神经细胞数目也减少,残留神经元变性。黑质纹状体区TH阳性多巴胺神经元较正常侧减少85%以上。
结论:血管内介入和外科手术颈内动脉注射MPTP的两种方法均可建立偏侧PD猴模型,通过行为学观察、阿朴吗啡诱发旋转试验观察到猴出现了偏侧的帕金森症状,MRI、SPECT及病理学检查证实在猴注药侧纹状体区有PD特征性改变,为进一步STN DBS研究提供了有用的实验模型。血管内介入较外科手术方法时间短,用药剂量少,可控性好,创伤小,更适合老年猴PD动物模型的建立。
关键词: 帕金森病 动物模型 猴 MPTP SPECT
第二部分:偏侧猴PD模型的脑深部电刺激
目的:通过观察丘脑底核慢性高频电刺激治疗猴偏侧PD模型后症状的改善情况,纹状体区DAT及D2R含量和葡萄糖代谢的变化,以及CSF中DA及其代谢产物的测定,探讨STN DBS对纹状体多巴胺神经递质的影响。
材料和方法:偏侧帕金森猴模型2只,在?
Parkinson’s disease (PD) is a progressive neurodegenerative disorder. The pathologic hallmark of the disease is the degeneration of dopaminergic neurons of the substantia nigra pars compacta, which leads to severe dopaminergic denervation of the corpus striatum. Deep brain stimulation of subthalamic sucleus (STN DBS) can improve most symptoms of mid or late stage PD patients with less complication, long term symptom regression, and decrease of antiparkinsonian drug dose. But many issues related to STN DBS remained to be answered, including basic questions as mechanism of action, long-term outcome and clinical indications.
The pathologic hallmark of PD is the degeneration of melanine-containing, dopaminergic neurons of the substantia nigra pars compacta, the dopaminergic deficit of the nigrostriatal system is accompanied by functional modifications of the other basal ganglia nuclei. Dopamine (DA) plays an important role in progession and treatment of PD. It is reported that striatal dopaminergic metabolism is increased by HFS of STN in 6-hydroxydopamine lesioned rats. But some clinical researchs indicated that STN DBS does not increase the striatal dopamine concentration in parkinsonian humans. The HFS which previous animal experimental studies used were short-time stimulation, and the PD animal model of rats induced by 6-hydroxy-dopamine (6-OHDA) is different markedly from PD of humans. There are many limits in clinical researchs. So we use nonhuman primate PD models induced by MPTP, which is most similar to idiopathic PD of human. And hemiparkinsonian monkeys were treated by long-term chronic high frequency stimulation of STN. We observed change of striatal dopamine function by single photon emission computed tomography (SPECT), positron emission tomography (PET), MRI and pathophysiology. We analyzed the potential mechanism of STN DBS by experimental data, which may lead to understanding of STN DBS as well as to new effective treatment modality for
delaying or stoping the procession of PD.
PartⅠ: Hemiparkinsonian monkey models induced by MPTP
Objective: Hemiparkinsonian monkey models can be induced by unilateral internal carotid artery infusion of 1-methy-4-phenyl-1,2,3,6-tetrahydropy-rindine (MPTP) with two different methods ,endovascular and direct surgical approach, are similar to that of Parkinsonian humans.The objective of this part is to provide PD monkey models for STN DBS experiment, simultaneously, to compare two kinds of methods.
Methods: Two healthy senior rhesus monkeys with wights ranging form 5~7kg were used in this study, all more than 10-year-old. There are two methods to establish monkey models of hemiparkinsonism with MPTP.
Endovascular approach: Two monkeys, after general anesthesia, were punctured of femoral artery. The internal carotid artery was catherized and MPTP saline (0.2mg/ml) was injected slowly under fluoroscopy.
Direct surgical approach: Two monkeys were included in this group. After general anesthesia, the right common carotid artery and bifurcation was exposed by blunt dissection. MPTP saline (0.2mg/ml) was injected into the right common carotid artery slowly after cliping of the external carotid artery.
All monkeys were evaluated after surgery according to a disability rating scale. The apomorphine evoked rotation was also tested. MRI verified the changes of substantia nigra and striatum of hemiparkinsonian monkeys were verified with MRI, and dopamine transporter (DAT) and D2 receptor (D2R) of striatum were measured using SPECT. The metabolism of dopamine of the lesioned side was compared with that of the normal side, which verified the impairment of nigrostriatal dopaminergic system induced by MPTP. After 6 months, both sides of striatum and substantia nigra of the monkey brain were cut into serial sections, and tyroxine hydroxylase (TH) immunohistochemistry study was performed. DA and its metabolites in cerebrospinal
fluid (CSF) were tested with high performance liquid chromatography and electrochemical detection (HPLC-ECD) pre- and post-infu
PD的病理学改变主要是黑质纹状体系统DA的减少伴有基底节神经核团的功能改变。多巴胺神经递质在PD的病程及治疗中起到了重要的作用。目前有研究表明,刺激鼠PD模型的STN核,可以增加纹状体区DA的释放和代谢。但是也有学者通过对临床病例的研究后提出,STN DBS治疗后并不能增加纹状体区DA的释放。因为6-羟基多巴(6-hydroxy-dopamine,6-OHDA)制备的鼠PD模型和人PD差别较大,并且动物试验研究所用的高频电刺激均为短期结果,临床病例研究有很多方面受到了限制。因此,本研究采用目前与人类PD最接近的MPTP灵长类动物模型,对猴PD模型STN核给予长期慢性高频电刺激,观察纹状体区域DA系统的变化,并结合了临床PD病人STN DBS手术前后的影像学资料进行对比研究,以确定STN DBS治疗后纹状体多巴胺神经递质的代谢变化,对STN核脑深部电刺激的作用机理和可能的神经保护机制作出合理的分析,为临床提高治疗帕金森病疗效,探索一种有效的方法延缓或阻止帕金森病的病程提供理论基础。
第一部分:偏侧猴帕金森病模型的制作
目的:分别采用血管内介入和手术两种方法颈内动脉注射1-甲基-4-苯基-1,2,3,6四氢吡啶(1-methy-4-phenyl-1,2,3,6-tetrahydropy-rindine,MPTP)制备偏侧猴PD模型,为下一步STN DBS实验提供帕金森病灵长类动物模型,并对两种制
备模型的方法进行比较。
材料和方法:动物均采用老年健康恒河猴,年龄均在10岁龄以上,体重在5～7Kg。制备模型药物采用MPTP。方法有以下二种:
血管内介入方法:恒河猴2只,全麻后在数字减影血管造影(digital subtraction angiography,DSA)下, Seldinger法股动脉穿刺,置5F鞘,4F单弯造影管超选颈内动脉造影,确认造影管置入颈内动脉后,缓慢注入MPTP生理盐水溶液(0.2mg/ml)。
直接手术方法:恒河猴2只,全麻后切开一侧颈部皮肤,经钝性分离暴露一侧颈总动脉,向上继续分离,显露颈动脉分叉部,暂时夹闭颈外动脉,缓慢注入MPTP生理盐水溶液(0.2mg/ml)。
术后均进行行为学观察和评估,指标包括运动障碍评分,阿朴吗啡诱发旋转实验等。MRI影像学检查验证注药侧黑质及纹状体区域信号强度变化,单光子放射计算机断层显像术 (single photon emission computed tomography, SPECT)对多巴胺转运体(Dopamine Transporter, DAT)及多巴胺D2受体(D2R)进行检查,与正常侧对比观察MPTP对于纹状体区多巴胺神经递质系统的损伤情况。待模型稳定后6个月,猴处死分别取两侧尾核、壳核和黑质组织,行病理切片,HE 和酪氨酸羟化酶(tyrosine hydroxylase ,TH)免疫组织化学染色。猴制作模型前后的脑脊液(cerebrospinal fluid,CSF)标本中的DA及其代谢产物的高效液相色谱-电化学法(high performance liquid chromatography and electrochemical detection , HPLC-ECD)检测。
结果:两种不同的方法制备偏侧PD模型后,行为学观察均发现猴自主运动明显减少,注药对侧肢体肌张力增高,部分猴伴有静止性震颤,运动迟缓,向患侧趴伏,步态不稳,运动障碍评分1个月后稳定在6分以上。阿朴吗啡 (apomorphine, APO)试验可诱发出特殊的向健侧的旋转动作。 MRI检查显示注药侧纹状体区域信号较对侧稍减低,未观察到注药侧黑质区域的信号改变。SPECT检查显示注药侧纹状体区的DAT明显降低,并一直保持较低状态,多巴胺D2受体在一个月时注药侧较正常侧摄取浓度明显增高, 3个月后仍保持稳定。
HPLC-ECD检测CSF中DA及其代谢产物二羟苯乙酸(dihydroxyphenylacetic acid ,DOPAC)和高香草酸(homovanillic acid ,HVA)含量发现给予MPTP1周后迅速下降,平均下降98%以上,并且一直保持在较低的水平。病理切片经HE 染色和TH免疫组织化学染色,发现注药侧黑质区域神经细胞变性减少,纹状体区域的神经细胞数目也减少,残留神经元变性。黑质纹状体区TH阳性多巴胺神经元较正常侧减少85%以上。
结论:血管内介入和外科手术颈内动脉注射MPTP的两种方法均可建立偏侧PD猴模型,通过行为学观察、阿朴吗啡诱发旋转试验观察到猴出现了偏侧的帕金森症状,MRI、SPECT及病理学检查证实在猴注药侧纹状体区有PD特征性改变,为进一步STN DBS研究提供了有用的实验模型。血管内介入较外科手术方法时间短,用药剂量少,可控性好,创伤小,更适合老年猴PD动物模型的建立。
关键词: 帕金森病 动物模型 猴 MPTP SPECT
第二部分:偏侧猴PD模型的脑深部电刺激
目的:通过观察丘脑底核慢性高频电刺激治疗猴偏侧PD模型后症状的改善情况,纹状体区DAT及D2R含量和葡萄糖代谢的变化,以及CSF中DA及其代谢产物的测定,探讨STN DBS对纹状体多巴胺神经递质的影响。
材料和方法:偏侧帕金森猴模型2只,在?
Parkinson’s disease (PD) is a progressive neurodegenerative disorder. The pathologic hallmark of the disease is the degeneration of dopaminergic neurons of the substantia nigra pars compacta, which leads to severe dopaminergic denervation of the corpus striatum. Deep brain stimulation of subthalamic sucleus (STN DBS) can improve most symptoms of mid or late stage PD patients with less complication, long term symptom regression, and decrease of antiparkinsonian drug dose. But many issues related to STN DBS remained to be answered, including basic questions as mechanism of action, long-term outcome and clinical indications.
The pathologic hallmark of PD is the degeneration of melanine-containing, dopaminergic neurons of the substantia nigra pars compacta, the dopaminergic deficit of the nigrostriatal system is accompanied by functional modifications of the other basal ganglia nuclei. Dopamine (DA) plays an important role in progession and treatment of PD. It is reported that striatal dopaminergic metabolism is increased by HFS of STN in 6-hydroxydopamine lesioned rats. But some clinical researchs indicated that STN DBS does not increase the striatal dopamine concentration in parkinsonian humans. The HFS which previous animal experimental studies used were short-time stimulation, and the PD animal model of rats induced by 6-hydroxy-dopamine (6-OHDA) is different markedly from PD of humans. There are many limits in clinical researchs. So we use nonhuman primate PD models induced by MPTP, which is most similar to idiopathic PD of human. And hemiparkinsonian monkeys were treated by long-term chronic high frequency stimulation of STN. We observed change of striatal dopamine function by single photon emission computed tomography (SPECT), positron emission tomography (PET), MRI and pathophysiology. We analyzed the potential mechanism of STN DBS by experimental data, which may lead to understanding of STN DBS as well as to new effective treatment modality for
delaying or stoping the procession of PD.
PartⅠ: Hemiparkinsonian monkey models induced by MPTP
Objective: Hemiparkinsonian monkey models can be induced by unilateral internal carotid artery infusion of 1-methy-4-phenyl-1,2,3,6-tetrahydropy-rindine (MPTP) with two different methods ,endovascular and direct surgical approach, are similar to that of Parkinsonian humans.The objective of this part is to provide PD monkey models for STN DBS experiment, simultaneously, to compare two kinds of methods.
Methods: Two healthy senior rhesus monkeys with wights ranging form 5~7kg were used in this study, all more than 10-year-old. There are two methods to establish monkey models of hemiparkinsonism with MPTP.
Endovascular approach: Two monkeys, after general anesthesia, were punctured of femoral artery. The internal carotid artery was catherized and MPTP saline (0.2mg/ml) was injected slowly under fluoroscopy.
Direct surgical approach: Two monkeys were included in this group. After general anesthesia, the right common carotid artery and bifurcation was exposed by blunt dissection. MPTP saline (0.2mg/ml) was injected into the right common carotid artery slowly after cliping of the external carotid artery.
All monkeys were evaluated after surgery according to a disability rating scale. The apomorphine evoked rotation was also tested. MRI verified the changes of substantia nigra and striatum of hemiparkinsonian monkeys were verified with MRI, and dopamine transporter (DAT) and D2 receptor (D2R) of striatum were measured using SPECT. The metabolism of dopamine of the lesioned side was compared with that of the normal side, which verified the impairment of nigrostriatal dopaminergic system induced by MPTP. After 6 months, both sides of striatum and substantia nigra of the monkey brain were cut into serial sections, and tyroxine hydroxylase (TH) immunohistochemistry study was performed. DA and its metabolites in cerebrospinal
fluid (CSF) were tested with high performance liquid chromatography and electrochemical detection (HPLC-ECD) pre- and post-infu
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