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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

亚氨基二丙腈（IDPN）长期给药。一种神经毒素，对大鼠产生持续的行为综合征，其特征是头部横向和垂直抽搐。传统上。这种IDPN诱导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，本研究还发现多巴胺（DA）和乙酰胆碱（ACh）神经系统的显着改变。DA和ACh神经元系统中的受体改变可能是继发性的，由于这些神经递质系统的异常。对不同脑区单胺能神经递质及其代谢产物的分析表明，多巴胺能和多巴胺能神经元系统之间的失衡在IDPN诱导的运动障碍的发病机制中起主要作用，即：e.与正常动物相比，IDPN处理的动物纹状体中的（DOPAC+HVA）/5 HIAA的比率显著更大，但海马中的（DOPAC+HVA）/5 HIAA的比率显著更小。IDPN诱导的皮肤功能障碍通过给予 ...更多信息左旋多巴增加多巴胺浓度，但完全被抑制多巴胺释放的蓝鲸肽抑制。在每天重复给予西曲肽6天后，头部交换次数减少至低水平，并保持显著低于治疗前水平，直至治疗后第4天。这些结果表明，蓝鲸肽对运动障碍的抑制是持久的。IDPN处理的动物的纹状体和海马中的（DOPAC+HVA）/5-HIAA的最初异常比率在用ceruletide处理后恢复正常，与头部抽搐的减少相对应。Ceruletide也产生了显着的影响，多巴胺能受体及其信使RNA表达的IDPN治疗的大鼠，在正常动物中只有轻微的影响。所观察到的ceruletide对受损神经元通路的有益作用表明其在IDPN诱导的运动障碍的动物模型中充当神经正常化剂。因此，蓝肽可用于治疗运动障碍，IDPN治疗的大鼠模型可用于阐明运动障碍的生化病理生理学和开发治疗药物。少