Biochemical and pharmacolotical pathogenesis of dyskinesia in the IDPN-treated rat model

IDPN 治疗的大鼠模型运动障碍的生化和药理学发病机制

基本信息

批准号：
01570449
负责人：
OGAWA Norio
金额：
$ 1.34万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1991
项目状态：
已结题

项目摘要

Chronic administration of iminodipropionitrile(IDPN). a neurotoxine, to rats produces a persistent behavioral syndrome characterized by lateral and vertical head twitching. Conventionally. this IDPN-induced dyskinesia has been considered to be due to abnormalities in the serotonin neuronal system. However, the present srudy also demonstrated marked alterations in the dopamine(DA)and acetylcholine(ACh)neuronal systems. Receptor alterations in the DA and ACh neuronal systems may be secondary due to abnormalities in these neurotransmetter systems. Assays of monoaminergic neurotransmitters and their metabolites in various brain regions-indicate that an imbalance between dopaminergic and serotonergic neuronal systems play a major role in the pathogenesis of the IDPN-induced dyskinesia, i. e. the ratio of(DOPAC+HVA)/5HIAA was significantly greater in the striatum but significantly smaller in the hippocampus of the IDPN-treated vs normal animals. IDPN-induced dyskinasia was enhanced by admini … More stration of levodopa, which increases dopamine concentration, but was completely inhibited by ceruletide, which inhibits dopamine release. After repeated daily dose of cedruletide for 6 days, the number of head swiches was reduced to low levels and remained significantly below pretreatment levels until the 4th posttreatment day. These results indicate that the inhibition of dyskinesia by ceruletide was long-lasting. Initially abnormal ratio of(DOPAC+HVA)/5-HIAA in the striatum and hippocampus of IDPN-treated animals returned to normal following treatment with ceruletide, corresponding with the reduction of head twitching. Ceruletide also exerted a marked effect on dopaminergic receptors and their messenger RNA expressions in the IDPN-treated rats, in contrast to only a slight effect in normal animals. The obsered beneficial effect of ceruletide on impaired neuronal pathways indicates that it acts as a neuro-normalizer in the animal model of IDPN-induced dyskinesia. Thus, ceruletide may useful in the treatment of dyskinesia, and the IDPN-treated rat model is useful for clarifing the biochemical pathophysiology of dyskinesia and developing drugs for its treatment. Less

长期给予伊米替次离子替代物（IDPN）。对大鼠的神经毒素产生的持续性行为综合征，其特征是侧向抽动。常规。这种IDPN引起的运动障碍被认为是由于5-羟色胺神经元系统的异常。然而，目前的Srudy还显示了多巴胺（DA）和乙酰胆碱（ACH）神经元系统的明显改变。 DA和ACH神经元系统中的受体改变可能是由于这些神经传输系统异常而是次要的。单胺能神经递质及其在各个大脑区域的代谢物的测定表明，多巴胺能和血清素能神经元系统之间的失衡在IDPN诱导的运动障碍的发病机理中起主要作用IDPN处理的与普通动物的。 IDPN诱导的性心理因素通过admin增强了……更多的左旋多巴策略，从而增加了多巴胺浓度，但被Ceruletide完全抑制，Ceruletide抑制了多巴胺释放。在每天重复剂量的固醇剂量6天后，头部旋转的数量降低到低水平，并显着低于预处理水平，直到治疗后第四天。这些结果表明，通过Ceruletide抑制运动障碍是长期的。最初，IDPN处理的动物的纹状体和海马中（DOPAC+HVA）/5-HIAA的异常比率在用ceruletide治疗后返回正常，与头部抽搐的减少相对应。 Ceruletide还对IDPN处理的大鼠中的多巴胺能受体及其信使RNA表达产生明显影响，与正常动物中仅略有影响相反。观察到的Ceruletide对受损神经元途径的有益作用表明它在IDPN诱导的运动障碍动物模型中充当神经纳程剂。这是Ceruletide在治疗运动障碍的治疗中可能很有用，并且经过IDPN处理的大鼠模型可用于阐明运动障碍的生化病理生理学并开发用于治疗的药物。较少的