摘要
多发性抽动症(Tourette's syndrome, TS)是一种慢性神经精神障碍性疾病,临床表现为不自主的、反复的肌肉抽动引发的运动性抽动(motor tics)和发声性抽动(vocal tics)。从目前的国内外研究进展来看：TS发病是一个较为复杂的多神经递质、多神经通路参与的神经精神障碍性疾病。从单一途径认识和治疗该病往往不能取得良好的临床疗效,这一方面是西医所面临的反复发作,难以治愈的棘手问题,同时也为中医治疗TS提供了广阔的应用前景。导师王素梅教授带领课题组一直致力于该病的基础实验与临床研究,并在“扶土抑木”大法指导下创制了治疗小儿TS的中药组方一一健脾止动汤,临床疗效确切。为进一步探讨该方治疗小儿TS的神经生化学机制及作用靶点,本课题拟在亚氨基二丙腈(IDPN)建立TS小鼠模型基础上,采用动物行为学、高效液相色谱法(HPLC)、酶联免疫吸附(ELISA)、Western blot等方法,对TS模型小鼠刻板行为、脑内纹状体多巴胺(DA)系统及谷氨酸(Glu)系统递质、受体、转运蛋白等指标进行检测,进一步揭示健脾止动汤治疗TS的作用机制。
本实验分为4个部分：(1)观察并比较TS模型鼠治疗前后刻板行为积分变化；(2)酶联免疫吸附法(ELISA)检测TS模型鼠纹状体DA、高香草酸(HVA)及多巴胺受体D1R、 D2R含量变化；(3)MicroPET技术检测TS模型鼠纹状体内多巴胺转运蛋白(DAT)分布情况；(4)高效液相色谱(HPLC)及Western blot法检测TS模型鼠纹状体Glu含量及谷氨酸转运蛋白GLT1表达水平。
动物模型建立及分组：
腹腔注射IDPN,350mg·kg-1,每天1次,连续7天,建立TS小鼠模型。80只雄性ICR小鼠,随机分为空白对照组、模型组、泰必利组、健脾止动汤组,每组20只。
主要实验结果如下：
1.健脾止动汤对TS模型鼠刻板行为的影响
腹腔注射IDPN后,造模小鼠均出现不同程度的头部抽动、旋转等刻板运动。与模型组相比,泰必利组和健脾止动汤组刻板行为平均积分呈显著下降趋势(P<0.05)。其中,健脾止动汤组改善模型小鼠刻板行为的疗效优于泰必利组(P<0.05),但与空白对照组相比,二组刻板行为积分仍处于较高水平(P<0.05)。
2.健脾止动汤对TS模型鼠纹状体DA、HVA、D1R、D2R含量的影响
与模型组比较,DA含量在泰必利组、健脾止动汤组和空白对照组中呈高表达(P<0.05)；HVA含量各组比较无统计学差异(P>0.05)；健脾止动汤组与模型组比较,D1R含量升高(P<0.05)；D2R含量各组比较无统计学差异(P>0.05)。
3.健脾止动汤对TS模型鼠纹状体DAT表达的影响
MicroPET冠状平扫结果显示,空白对照组小鼠双侧纹状体区示踪物11C-β-CFT呈高亮聚集分布,大体上呈均一对称分布特点,而模型组纹状体区11C-β-CFT呈低密度聚集分布。药物干预后,泰必利组和健脾止动汤组11C-β-CFT重摄取率远大于模型组(P<0.01),且健脾止动汤组重摄取率高于泰必利组(P<0.05)。
4.健脾止动汤对TS模型鼠纹状体Glu、GLT1含量的影响
与空白对照组相比,模型组小鼠纹状体Glu显著升高(P<0.05)。药物干预后,泰必利组和健脾止动汤组Glu含量均呈下降趋势,健脾止动汤组下降程度较泰必利组显著(P<0.05),接近于正常水平(P>0.05)。
与空白对照组相比,模型鼠纹状体GLT1蛋白表达显著升高(P<0.05)。药物干预后,泰必利组、健脾止动汤GLT1表达均较模型组有所下调(P<0.01),但二者间未见显著差异(P>0.05),且二者表达量远高于空白对照组(P<0.01)。
结论：健脾止动汤针对IDPN诱发的TS模型鼠具有确切的抗抽动疗效。TS模型鼠纹状体DA及Glu系统内存在神经生化学改变。主要表现为：DA及其受体表达紊乱,DAT呈现低表达,Glu及其转运体GLT1含量升高。健脾止动汤可能通过上调TS模型鼠纹状体内DAT,增加突触间隙DA重摄取；降低Glu含量,抑制黑质-纹状体通路的运动兴奋性,从DA和Glu双系统、多靶点来发挥抗抽动的作用。
Tourette syndrome (TS) is a chronic neurobehavioral disorder characterized by involuntary motor and phonic tics. On account of the research advances at home and abroad in recent years, the mechanism of TS relates to complicated and multiple neurotransmitters and neural pathways. It could hardly obtain satisfactory clinical curative effect just from a single viewpoint for perception and treatment. So, on the one hand, its recurrence and refractoriness has become a problem which western medicine has to confront. On the other hand, it provides a broad prospect for traditional Chinese medicine (TCM) that could exert its unique therapeutic advantage. My tutor, Professor Wang sumei accompanied by her team has committed to the basic experiments and clinical research on TS for years. Following the principle of supporting Spleen and inhibiting Liver, she creates the Chinese Medicine Formula "Jian-Pi-Zhi-Dong Decoction (JPZDD)" which has been testified as an effective anti-tics agent in cl inic.
In order to further exploring the neurochemical mechanism of TS and targets of the formula, this subject aims to induce TS model by iminodipropionitrile (IDPN), basing on the techniques such as the animal ethology, high performance liquid chromatography (HPLC), enzyme linked immunosorbent assay (ELISA) and Western blot, study the influences of the formula on the stereotyped behavior of TS mice model, and detect the contents of the transmitters, receptors and transporters belonging to the dopamine (DA) and glutamic acid (Glu) systems in the striatum.
This subject divided into four parts. The first part, the scores of stereotyped behavior of TS model mice before and after diverse administrations were contrast. The second part, the levels of DA, homovanillic acid (HVA), dopamine receptors (D1R, D2R) were detected by means of ELISA. The third part,11C-β-CFT binding which manifests the distribution of Dopamine transporter (DAT) at bilateral striatum was observed. The fourth part, the level of Glu and expression of glutamate transporter (GLT1) were detected by HPLC and Western blot.
Eighty ICR mice (male, aged4weeks,18±2g) were housed10per cage in an air-conditioned animal room with12h light/dark cycle, allowed access to water and food ad libitum, maintained in a constant temperature20±2℃and humidity50±5%, fed for1w before generating TS model. After1w, mice were randomly divided into the saline group (control group)(n=20) and the TS model group (n=60). The former were intraperitoneal ly injected (i. p.) with saline (0.9%)(15ml·kg-1); the later were injected with IDPN (350mg·kg-1, i.p.) once a day for7consecutive days. IDPN mice model group were further divided into3groups:IDPN group (n=20), Tiapride (Tia) group (n=20), and JPZDD group (n=20). The et ho logical score between each group was balanced referring to the evaluating grade of stereotypy. The saline and IDPN groups were gavaged with saline (0.9%) at20ml·kg-1, the group with Tia at50mg·kg-1, and the group with JPZDD at20g·kg□1respectively once a day for8consecutive weeks.
The results show as followed:
1. The effect of JPZDD on the stereotyped behavior of TS model mice.
TS model mouse induced by IDPN showed abnormal stereotypes in different degrees. Remarkably, severity of stereotypes in either Tia or JPZDD group decreased significantly as compared to IDPN alone group (P<0.05). Comparison between administrated groups showed the average score of JPZDD was lower than Tia (P<0.05) at the end of experiment although it was still higher than that of saline group (P<0.05).
2. The effect of JPZDD on the contents of DA, HVA, D1R, D2R in the striatum of TS model mice.
Compared with IDPN group, the level of DA in the other3groups were highly expressed (P<0.05); the levels of HVA and D2R in4groups showed no differences (P>0.05); Compared with IDPN group (P>0.05), the level of D1R in JPZDD group rose obviously (P<0.05).
3. The effect of JPZDD on the expression of DAT in the striatum of TS model mice.
Coronal scans manifested by PET imaging showed high tracer accumulation at bilateral striatum regions in saline group with uniform distribution and symmetric morphous. Marked fuzzy images and low accumulation of11C-β-CFT were observed in TS model mice. After8w, the uptake ratio of11C-β-CFT was significantly higher in both Tia and JPZDD treated groups than that in IDPN group (P<0.01). Furthermore, the uptake ratio of11C-β-CFT in JPZDD group was significantly higher than that in Tia group (P<0.05).
4. The effect of JPZDD on the levels of Glu, GLT1in the striatum of TS model mice.
Compared with saline group, the levels of Glu and GLT1in IDPN group were highly expressed (P<0.05). They declined to lower levels in administrative groups. Hereinto, the expression of Glu in JPZDD group down-regulated more obviously than that in IDPN group (P<0.05), and the level of GLT1in Tia and JPZDD groups decreased more apparently compared with IDPN group (P<0.01), but still higher than that in saline group (P<0.01).
Taken together, JPZDD is an effective formula for treating TS and it is probable that the changes of neurobiochemistry involving DA and Glu systems exist in the stria tum of TS model mice. They mainly manifes ted as:abnormal expressions of DA and DRs; the lower expression of DAT and higher levels of Glu and GLT1. JPZDD may up-regulate the DAT expression in the striatum which indirectly reinforces the recapture of DA back to the presynaptic membrane. It also decreases the content of Glu which direct ly inhibit the motor excitability during substantial nigra-striatum pathway. It may further reflect the anti-tics effect of JPZDD owes to double systems and multiple targets.
引文
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