Haloperidol protects striatal neurons from dysfunction induced by mutated huntingtin in vivo
Haloperidol protects striatal neurons from dysfunction induced by mutated huntingtin in vivo
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DOI：
10.1016/j.nbd.2007.07.028
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发表时间：
2008-01-01
影响因子：
6.1
通讯作者：
Caboche, Jocelyne
中科院分区：
文献类型：
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作者：
Charvin, Delphine;Roze, Emmanuel;Caboche, Jocelyne
亨廷顿病(HD)是由亨廷顿蛋白N-末端区域的异常多谷氨酰胺延伸引起的。这种突变导致纹状体投射神经元的优先变性。我们先前在体外证明，多巴胺能D2受体的刺激与突变的亨廷顿蛋白(ExpHtt)协同作用，增加聚集形成和纹状体死亡。在目前的工作中，我们将这些观察扩展到一个基于慢病毒介导的expHtt在大鼠纹状体中表达的体内系统。通过DARPP-32和Neun染色分析，早期和长期使用D2拮抗剂氟哌啶醇癸酸酯可以保护纹状体神经元免受exHtt诱导的功能障碍。氟哌啶醇治疗还可以减少聚集物的形成，这一效果会随着时间的推移而保持。这些发现表明，D2受体的激活参与了expHtt对纹状体功能的有害影响，并可能是改变HD后续神经病理过程的一个有趣的早期靶点。(C)2007 Elsevier Inc.保留所有权利。
Huntington's disease (HD) results from an abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation causes preferential degeneration of striatal projection neurons. We previously demonstrated, in vitro, that dopaminergic D2 receptor stimulation acted synergistically with mutated huntingtin (expHtt) to increase aggregate formation and striatal death. In the present work, we extend these observations to an in viva system based on lentiviral-mediated expression of expHtt in the rat striatum. The early and chronic treatment with the D2 antagonist haloperidol decanoate protects striatal neurons from expHtt-induced dysfunction, as analyzed by DARPP-32 and NeuN stainings. Haloperidol treatment also reduces aggregates formation, an effect that is maintained over time. These findings indicate that D2 receptors activation contributes to the deleterious effects of expHtt on striatal function and may represent an interesting early target to alter the subsequent course of neuropathology in HD. (c) 2007 Elsevier Inc. All rights reserved.