CN113229212B - 一种双位点联合注射6-OHDA和α-synuclein建立大鼠帕金森病模型的方法 - Google Patents
一种双位点联合注射6-OHDA和α-synuclein建立大鼠帕金森病模型的方法 Download PDFInfo
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Abstract
本发明公开了一种双位点联合注射6‑OHDA和α‑synuclein建立大鼠帕金森病模型的方法,该方法包括以下步骤:根据大鼠的脑定位图谱获得大鼠黑质的位点,两位点坐标为:前囟后0.48cm,脑中线向右0.11cm,在硬脑壳表面下0.8cm;前囟后0.48cm,脑中线向右0.19cm,在硬脑壳表面下0.75cm两位点处分别注射6‑OHDA和AAV‑α‑synuclein。造模后四周对造模大鼠头部皮下注射盐酸阿朴吗啡进行旋转实验检测,大鼠向健康侧旋转并转圈数大于200r/30min,即为造模成功。转圈数小于规定数值即认为造模失败。本发明选取了黑质较大位置,采用两个位点不同深度注射药物可较好的损伤黑质的多巴胺神经元。可提高造模成功率,造模四周达到90%以上的成功率。目前报道的其他位点的成功率一般都低于80%,提高了造模成功率。
Description
技术领域
本发明涉及一种建立大鼠帕金森病模型的方法,具体涉及一种双位点联合注射6-OHDA和α-synuclein建立大鼠帕金森病模型的方法,属于生物学领域。
背景技术
帕金森氏病(Parkinson’s disease,PD)是继老年性痴呆(Alzheimer’sDisease)后的第二大神经退行性疾病,在65-69岁的老年人群中发病率约占0.5%-1%,在80岁以上的老年人中发病率能达到1%-3%。PD的主要病理改变是中脑多巴胺能神经元中发生变性蛋白聚集小体(LewyBodies)导致多巴胺能神经元凋亡,在临床上引起静止性震颤,运动迟缓,肢体僵硬及步态不稳及其它非运动症状。严重影响患者的生活治疗,并且导致沉重的医疗负担。
虽然近些年来,随着对帕金森病研究的深入,已有一些治疗方法能够减轻疾病的某些症状,但是都达不到彻底治愈的目的,目前的治疗实质上主要是提高病人的生活质量和工作能力。在帕金森病的各种治疗方法中仍以药物治疗为主。但是目前没有根治帕金森病的药物,且随着患病时间的延长病情逐渐加重。因此,更深入的研究PD的发病机制和治疗方法很有必要,而稳定高效的动物模型是深入研究该疾病的前提。
目前较为公认的建立PD模型的方法主要有两种:一种是应用6-羟基多巴胺(6-OHDA)注入黑质纹状体系统来损毁大鼠黑质纹状体系统DA能神经元所制成的模型;另一种是运用MPTP制备猴等灵长类动物模型和C57B小鼠PD模型,因为大鼠相对灵长类成本低,样本数量不受限制;又比小鼠体积大、相对容易定位,所以很多学者选择注射6-OHDA于大鼠脑内建立PD动物模型。
6-OHDA与多巴胺受体只差一个羟基,可形成自由基,是一种神经毒素,能够抑制线粒体氧化呼吸链复合物I并激活caspase而启动了细胞凋亡过程,从而选择性的损毁DA能神经元。DA能神经元投射有两条通路:即黑质-纹状体通路和新边缘系统通路,前者是黑质与纹状体相连接,后者是中脑腹侧背盖区与纹状体相联系。已往很多报道选择通路中的黑质致密部、内侧前脑束、纹状体、中脑腹侧背盖区的一个或两个位点进行PD造模,但由于黑质致密部、内侧前脑束、纹状体和中脑腹侧背盖区的不同位点的选择对PD造模的成功率影响很大,目前已报道的PD造模成功率多在80%以下,严重制约了对PD发病机制和治疗方法的研究。
发明内容
有鉴于此,本发明提供了一种双位点联合注射6-OHDA和α-synuclein建立大鼠帕金森病模型的方法,可以得到早期帕金森症状的动物模型,采用本发明的制备方法,造模四周的成功率在90%以上,具有造模成功率高,造模时间短等优点。
为了实现上述目的,本发明采用如下技术方案:
一种双位点联合注射6-OHDA和α-synuclein建立大鼠帕金森病模型的方法,其步骤如下:
将大鼠经腹腔注射麻醉剂后,固定于脑立体定位仪上。
根据实验大鼠的脑立体定位图谱获取内侧前脑束位点,位点坐标为前囟后0.48cm,脑中线向右0.11cm,硬脑膜表面下0.8cm、前囟后0.48cm,脑中线向右0.19cm,硬脑膜表面下0.75cm,使用动物颅钻,钻透颅骨且不损伤硬脑膜,注射器垂直入颅,缓慢进针,在两处标记位点注射共分别注射6-OHDA和AAV-α-synuclein,术中时刻观察大鼠生命体征;
注射后连续三天注射青霉素5万单位,以防止感染,建造动物模型;
造模后20天对实验大鼠注射阿朴吗啡诱发向左侧的旋转行为,注射后10min大鼠就会出现行为学改变,连续记录40min:旋转时多数以左侧后肢为支点,身体环曲呈“C”状,首尾相接,伴探嗅觅食样动作,有的旋转速度过快甚至出现翻转,频率为200圈/半个小时以上视为造模成功。
进一步,6-OHDA和AAV-α-synuclein的注射速度保持为1μl/min,注射完成后留针5min。
进一步,6-OHDA的注射量为2.5μl,AAV-α-synuclein的注射量为1μl。
进一步,6-OHDA的浓度为5μg/μl,AAV-α-synuclein的浓度为5μg/μl,AAV-α-synuclein的病毒滴度为1.5X1012vg/ml。
进一步,实验大鼠为体重为200-240g的实验大鼠。
进一步,阿朴吗啡的注射量为0.25mg/kg。
本发明还提供了一种帕金森病大鼠模型在帕金森病治疗药物中的应用,其中,帕金森病大鼠模型由上述建立方法得到。
本发明的有益效果在于,采用本发明的制备方法,造模四周的成功率在90%以上,具有造模成功率高,造模时间短等优点。
附图说明
图1为本发明实施例1为阿朴吗啡检测造模成功大鼠向左旋转结果图;
图2为本发明实施例16-OHDA注射到大鼠侧黑质区经酪氨酸羟化酶染色免疫反应结果图;
图3为本发明实施例1转棒疲劳仪。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
在以下实施例中,脑立体定位仪选用瑞沃德脑立体定位仪;
实验大鼠选择体重区间在200-240g之间的大鼠;
6-OHDA的浓度为5μg/μl,AAV-α-synuclein的浓度为5μg/μl,AAV-α-synuclein的病毒滴度为1.5X1012vg/ml。
实施例1
双位点联合注射6-OHDA和α-synuclein建立大鼠帕金森病模型的方法,其步骤如下:
将大鼠腹腔注射麻醉后,剪去头顶部毛发,固定于脑立体定位仪上(双侧耳杆尖端插入外耳道,使头部固定保持水平,并尽量使前、后囟保持同一平面上)。75%酒精消毒,切开头皮、暴露头骨。采用小动物颅钻小心钻透定位处的颅骨不要损伤硬脑膜,参照Paxinos等主编的《大鼠脑立体定位图谱》。
根据前囟后0.48cm,脑中线向右0.11cm,在硬脑膜表面下0.8cm;前囟后0.48cm,脑中线向右0.19cm,在硬脑膜表面下0.75cm标记好位点。
确定好的坐标将吸入药物的微量注射器连接于微量推进器上向SNc和VTA分别注射配置好的2.5μl 6-OHDA、1μl AAV-α-synuclein,垂直入颅,缓慢进针,6-OHDA和AAV-α-synuclein的注射保持速度为1μl/min,留针5min,缓慢退针1mm/min,术中观察大鼠生命体征。
常规缝合,三天连续腹腔注射青霉素5万单位以防治感染。建造动物模型。在10天后腹腔注射APO诱发大鼠向左侧(健侧)的旋转行为。
造模后20天对实验大鼠注射0.25mg/kg阿朴吗啡诱发向左侧的旋转行为,注射后10min左右大鼠就可出现行为学改变,连续记录30min:旋转时多数以左侧后肢为支点,身体环曲呈“C”状,首尾相接,伴探嗅觅食样动作,有的旋转速度过快甚至出现翻转,大鼠向左旋转频率为200圈/半个小时以上视为造模成功,左旋结果图如图1,造模过程及结果记录如下表1。
表1造模结果记录表
造模成功率可达到90%左右。并通过动物的旋转行为及病理、生化可以得以验证模型的成功,结果如图2。图2中,左边是正常脑组织,右侧是损伤侧。图2可知,右侧注射药物后造成多巴胺神经元细胞减少,6-OHDA注射到大鼠侧黑质区经酪氨酸羟化酶染色免疫反应阳性细胞较健康侧明显减少。
注射药物和病毒后,使用转棒疲劳仪检测,转棒速率为4圈/分钟。分别分为模型组和对照组,模型组为造模成功,对照组是未手术处理的正常大鼠。结果如图3所示,由图3可知,随着注射药物和病毒的周数时间越长,动物的转棒时间越短。
Claims (4)
1.一种双位点联合注射6-OHDA和α-synuclein建立大鼠帕金森病模型的方法,其特征在于,步骤如下:
根据实验大鼠的脑立体定位图谱获取内侧前脑束位点,位点坐标为前囟后0.48cm,脑中线向右0.11cm,硬脑膜表面下0.8cm、前囟后0.48cm,脑中线向右0.19cm,硬脑膜表面下0.75cm,在两处标记位点分别注射6-OHDA和AAV-α-synuclein;
注射后连续三天注射青霉素5万单位,建造动物模型;
造模后20天对实验大鼠注射阿朴吗啡诱发向左侧的旋转行为,实验大鼠旋转行为为200圈/半个小时视为造模成功;
所述6-OHDA的注射量为2.5μl,所述AAV-α-synuclein的注射量为1μl;
所述6-OHDA的浓度为5μg/μl,所述AAV-α-synuclein的浓度为5μg/μl,所述AAV-α-synuclein的病毒滴度为1.5×1012vg/ml;
所述阿朴吗啡的注射量为0.25mg/kg。
2.根据权利要求1所述的双位点联合注射6-OHDA和α-synuclein建立大鼠帕金森病模型的方法,其特征在于,注射6-OHDA和AAV-α-synuclein的注射速度保持为1μl/min,注射完成后留针5min。
3.根据权利要求1所述的双位点联合注射6-OHDA和α-synuclein建立大鼠帕金森病模型的方法,其特征在于,所述实验大鼠为体重为200-240g的实验大鼠。
4.一种帕金森病大鼠模型在帕金森病治疗药物中的应用,其特征在于,所述帕金森病大鼠模型由权利要求1-3任一项所述建立方法得到。
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