托吡酯治疗Tourette综合征大鼠的疗效及机制研究

Curative effect and possible mechanisms of topiramate in treatment of Tourette syndrome in rats

目的目前研究认为Tourette综合征(TS)的发病与多巴胺(DA)、兴奋性氨基酸(EAA)等神经递质障碍有关。近年报道托吡酯等抗癫癎药对此综合征有一定的疗效,但其具体的作用机制尚不十分清楚。该研究通过测定亚氨基二丙腈(IDPN)诱发的头部抽动大鼠模型脑内游离DA和血浆EAA含量的改变,探讨TS发病与神经递质异常之间的关系并探讨托吡酯对该模型的作用。方法将48只Sprague-Dawley大鼠随机分为空白对照组、模型组、氟哌啶醇组(0.5 mg/kg)、托吡酯I组(5 mg/kg)、托吡酯II组(10 mg/kg)、托吡酯III组(20 mg/kg)。采用腹腔注射IDPN(每日150 mg/kg,1次/d,连续7 d)诱导大鼠头部抽动作为Tourette综合征动物模型。托吡酯或氟哌啶醇给药35 d后分别采用ELISA法和HPLC法测定脑组织游离DA和血浆EAA的含量。结果与空白对照组相比,IDPN诱导的头部抽动大鼠脑组织游离DA含量明显降低、血浆EAA含量明显升高(P<0.05);与模型组相比,中、大剂量托吡酯给药35 d后能明显减少IDPN所致的大鼠头部抽动行为(P<0.05),升高脑内游离DA的含量;同时大剂量托吡酯组还伴随着血浆EAA水平的降低(P<0.05),作用效果与阳性对照药氟哌啶醇一致。结论TS的发生可能与中枢DA受体超敏感和血浆EAA的过度作用有关。托吡酯可减轻IDPN诱导的大鼠抽动行为,其作用机制可能与其抑制脑内DA与DA受体的结合以及抑制血浆EAA的释放和分泌有关。

Objective The pathogenesis of Toutette syndrome （TS） is associated with the disorders of neurotransmitters, such as dopamiue （DA） and excitatory amino acids （EAA）. Antiepileptic drugs such as topiramate have shown some effects on TS, but the mechanism has not been clearly identified. The objective of the research was to evaluate the relationship between the pathogenesis of TS and abnormality of neurotransmitters by determining the levels of brain free DA and plasma EAA in iminodipropionitrile （IDPN） induced head twitch response （HTR） rats, and to investigate the effects of topiramate on HTR induced by IDPN. Methods Forty-eight Sprague-Dawley rats were randomly divided into six groups： blank control, TS model, and haloperidol-（0.5 mg/kg） and topiramate-treated （5, 10 and 20 mg/kg）. HTR was induced by 7-day peritoneal injections of IDPN （ 150 mg/kg daily） and was used as TS model. Brain free DA levels and plasma levels of EAA were measured using ELISA and high performance liquid chromatography respectively 35 days after haloperidol or topiramate administration. Results Brain flee DA levels were significantly lower and plasma EAA levels were significantly higher in the TS model group compared with those in the blank control group （P 〈0.05 ）. Topiramate of 10 and 20 mg/kg significantly decreased the frequency of IDPN-induced HTR and significantly increased the level of brain free DA when compared with the TS model group （P 〈0.05）. Topiramate of 20 mg/kg treatment as haloperidol treatment significantly decreased plasma EAA levels compared with the TS model group （P 〈 0.05）. Conclusions The pathogenesis of TS is related to the super-sensitivity of DA receptor in the center nervous system and the over-effect of plasma EAA. Topiramate can reduce IDPN-induced HTR, probably through the iuhibition of DA and DA-receptor combination in the brain and the secretion and release of plasma EEA.