熄风静宁冲剂治疗Tourette Syndrome（抽动—秽语综合征）的药效及机理研究

【作者】 杨龙飞；

【导师】 潘思源；

【作者基本信息】 北京中医药大学 ， 中西医结合基础， 2003， 硕士

【摘要】 Cilles de la Tourette综合征，又称慢性多发性抽动、抽动-秽语综合症，是一种运动障碍病，抽动常常会突然发作，甚至发生在讲话或工作中，行为严重时可影响到周围环境，这些症状均给患者带来明显痛苦，使其社交、职业或其它重要功能显著受损。根据对病因和并发症状的研究，常用的西药有神经阻滞剂氟哌啶醇、哌迷清、氟奋乃静、三氟拉嗪等，这些药物能减轻Tourette征的运动抽动和发声抽动症状，但常有锥体外系副作用，如运动不全、震颤、肌强直等，也可发生静坐不能、意识障碍等，且停药后原症状易复发并有可能出现症状加重的情况。因此积极利用我国传统医药来认识和治疗该症，开发新的制剂具有实际意义。 本研究观察了熄风静宁冲剂对小鼠一般神经药理和Tourette征动物模型的作用，以及大、小鼠脑内单胺类神经递质的变化。 1．静宁冲剂剂的一般中枢药理作用 1．1 对小鼠自主活动的影响 静宁冲剂一天及连续五天给药，用运动量测定装置观测给药2小时后小鼠的自主活动情况。实验结果表明，一次给药，静宁冲剂10g／kg、5g／kg均能抑制正常小鼠的自主活动(P＜0.01，P＜0.05)，但连续给药五天静宁冲剂各组小鼠的自主活动与对照组相比均无统计意义。 1．2 对戊巴比妥和水合氯醛催眠作用的影响 静宁冲剂一天及连续五天给药，小鼠腹腔注射戊巴比妥(40mg／kg)或水合氯醛(400mg／kg)，记录小鼠的睡眠开始时间和觉醒时间，计算睡眠持续时间，观察静宁冲剂对戊巴比妥及水合氯醛的催眠作用是否有协同作用。实验结果显示，一次给药静宁冲剂10g／kg、5g／kg均能显著延长小鼠的睡眠时间(P＜0.01)，连续给药五天静宁冲剂10g／kg组可显著延长小鼠的睡眠时间(P＜0.01)。 1．3 对戊四氮致小鼠惊厥的影响 静宁冲剂一天及连续五天给药，小鼠腹腔注射戊四氮(110mg／kg)，观察小鼠的惊厥潜伏期和死亡时间，计算死亡率。结果显示，静宁冲剂不能对抗戊四氮引起的惊厥。 1．4 对东莨菪碱(Sco)致小鼠自主活动增加的影响 静宁冲剂一天及连续五天给药，小鼠腹腔注射Sco，用运动量测定装置记录小鼠自主活动数。结果显示，一次给药实验，静宁冲剂各剂量组均可抑制东莨菪碱引起的自主活动增多(P＜0.01，P＜0.05)，但连续给药五天后，各组结果均无统计意义。4 熄风静宁冲剂治疗Tourette征的药效及机理研究 2．静宁冲剂对Tourette征动物模型的影响 2．1对苯丙胺（AmPh）所致的小鼠自主活动增加的影响 静宁冲剂一天及连续五天给药，小鼠腹腔注射苯丙胺，20分钟后用观测小鼠的自主活动惰况。结果发现，连续五天给药静宁冲剂sg／kg、2．sg儿g组可显著减少苯丙胺引发的小鼠自主活动增多（P叩．01），但一次给药对苯丙胺引起的小鼠活动增加没有对抗作用。 2．2对阿朴吗啡u）所致的小鼠攀爬行为的影响 静宁冲剂连续给药五天后，小鼠腹腔注射阿朴吗啡，观察小鼠的攀爬时间。结果显示静宁冲剂各剂量组均可减少小鼠的攀爬时间（P＜0．01）。 2．3对阿朴吗啡所致的大鼠定型活动的影响 静宁冲剂给药一天、五天，大鼠腹腔注射阿朴吗啡，观察其定型活动，并评分。每4min评分一次，共评4次；各次累加的评分和为总评分，评分标准按：《药理实验方法学》（人民卫生出版社，1991年，第二版）中定型活动强度评级记分法。结果发现，静宁冲剂各剂量组连续给药五天能显著抑制阿朴吗啡引起的定型活动，评分减少（P＜O．“，P＜0．01）。 2．4连续五天给药对大鼠旋转模型的影响 用体重180克左右的大鼠，麻醉后在定位仪上确定黑质致密区，然后在颅骨相对应位置打一小孔，将新鲜配制的6－OHDA溶液4 yi注射入一侧黑质；手术一月后进行药物试验，实验在隔音室内进行，先将大鼠放在凹底铝锅中适应 10m i n，腹腔注射APO，观察其旋转行为，静宁冲剂连续五天给药后再观察其旋转行为，用自身比较，t检验来检测静宁冲剂是否能对抗这种旋转。结果显示，静宁冲剂4g儿g能显著对抗这种旋转行为（P＜0．01）。 2．5对卜羟色胺酸门叫TP）所致的小鼠甩头行为的影响 静宁冲剂连续五天给药，小鼠腹腔注射5－羟色胺酸（SHTP），记录5叫n内甩头次数。结果发现，静宁冲剂10g儿g；2．sg儿g均能减少 卜羟色胺酸引发的甩头次数 （P＜0．05）。 3．静宁冲剂对小鼠脑内单胺类神经递质的影响 3．1对正常小鼠脑内单胺类神经递质的影响 静宁冲剂一天及连续五天给药，给药Zh后取脑，用高效液相电化学法（HPLC一ECD）测脑内单胺类神经递质及其代谢产物的含量。结果，一次给药静宁冲剂sg从g可减少脑内的卜羟色胺水平（Po．05），连续给药五天，静宁冲剂 109八g、2．sg儿g可减少卜羟色胺代谢产物 SHIAA（5－Hydroxyindoleacetic acid）的水平（P＜0．05），静宁中文摘要5冲剂 sg／kg、2．sg／kg 可增加 多巴胺代谢产物 WA（Homovmillic acid）的水平 （P＜0．05）。 3．2对大鼠定型活动模型脑纹状体DA及HVA含量的影响。 静宁冲剂?更多还原

【Abstract】 Tourette Syndrome (TS) is named for Gilles de la Tourette, a French physician. This disease is a type of tic disorder. Tourette Syndrome is an inherited neurological disorder characterized by multiple involuntary movements and uncontrollable vocalizations called tics. The tics always appear suddenly even though during the speaking and working. The tics behavior can also affect the other people under the severe condition. Patients with Tourette Syndrome often come to feel that their social isolation, vocational or academic failure. According to the research of etiological factor and associated symptoms, the frequently used drugs include Haloperidol, pemozide, flumezine, fluazine and so on. Although these drugs can decrease the motor tics and vocal tics, they can not avoid the extrapyramidal effects such as convulsion, tardive dyskinesia, akathisia, and conscious disturbance. If these drugs are not used the original symptoms can be possibly aggravated. Therefore it is important to develop a new medicine of the TS treatment from the Traditional Chinese Herbals.In this work I studied the pharmacological effects and possible mechanisms of Xi Feng Jing Ning Recipe (XFJNR) in treating TS.Results:1. General pharmacological effect of XFJNR on central system1.1 Effect of XFJNR on spontaneous locomotor activity of mice: Mice were single and successively 5 days administrated with XFJNR. Results showed that the locomotor activities in the mice treated with XFJNR at the doses of 10g/kg, 5g/kg were decreased compared with control (P<0.01, P<0.05)1.2 Hypnotic effect of XFJNR on mice: XFJNR was administrated single and successively 5 day to the mice. Pentobarbital ip or chloral hydrate was ip after 1.5 hours at the last dosage. Results showed that the pentobarbital- and chloral hydrate-induced-hypnosis period was prolonged in mice receiving XFJNR at the doses of 10g/kg, 5g/kg (P<0.01).1.3 Effect of XFJNR on increased locomotor activity of mice induced by scopolamine: Experimental animals were injected Scopolamine to induce the high spontaneous activity. Results showed that single administration, three doses of XFJNR (10g/kg, 5g/kg, 2.5g/kg) could decrease the increased locomotor activity induced by scopolamine (P<0.05 compared with control).2. Effects of XFJNR on TS model2.1 Effect of XFJNR on increased locomotor activity of mice induced by amphetamine: Experimental animals were injected Amph to induce the increased spontaneous activity. It was found that XFJNR 5g/kg, 2.5g/kg for five days administration could decrease the amphetamine-induced high locomotor activity (P<0.01, compared with Amph group).2.2 Effect of XFJNR on increased climbing behavior of mice induced by apomorphine:Experimental animals were injected Apo to induce the increased climbing behavior. It was found that three doses of XFJNR for five days administration could decrease the apomorphine-induced climbing behavior in rats (P<0.01. compared with APO group).2.3 Effect of XFJNR on Rat’s stereotyped behavior: Experimental animals were randomly divided into six groups, the normal control group, the APO group, the Haloperidol treated group, and the XFJNR treated groups (8g/kg, 4g/kg, Ig/kg). At the end of the first and fifth treatment, except the normal control group, each group administrated apomorphine to arouse the stereotyped behavior. The behavior scores were record to evaluate the effect of the treatment. Compared with APO group, the scores of stereotyped behavior decreased by the treatment of XFJNR (P<0.05,P<0.01).2.4 Effect of XFJNR on Rotational Behavior in Rats: Experimental animals were unilateral nigral lessoned (right side) by micro-injection of 6-OHDA. The rats with obvious rotational behavior induced by APO were chosen to carry out the test. It was found that XFJNR could significantly antagonize the rotational behavior (P<0.01). and was consistent with the effect of positive drug-llaloperidol.2.5. Effect of XFJNR on head-twitch model induced by 5-HTP in mice: Experim更多还原