纹状体GluN2A基因抑制可减少左旋多巴诱导的帕金森大鼠异常不自主运动。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-07-29 DOI:10.1016/j.neuropharm.2025.110616

Taiki Yabumoto , Brik A. Kochoian , Stefano Coletta , Oskar Laur , Xinping Huang , Cassandra A. Bure , Christopher Ware , Peng Jin , Stephen F. Traynelis , Stella M. Papa

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引用次数: 0

摘要

左旋多巴诱导的运动障碍（LID）是长期左旋多巴治疗帕金森病（PD）的常见致残并发症。LID的发展与纹状体回路中由多巴胺和谷氨酸信号失调引起的适应性不良可塑性机制有关。NMDAR亚基2A （GluN2A）在慢性左旋多巴治疗中的上调被认为在皮质纹状体突触改变中起作用。我们通过在半帕金森大鼠纹状体中注射shRNA载体，研究了GluN2A基因选择性沉默的运动效应。纹状体GluN2A敲除显著减少异常不自主运动（AIMs），同时维持左旋多巴的治疗效果。这些发现表明，有针对性地调整纹状体NMDAR亚基组成可能是一种有希望的PD长期治疗策略。

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Striatal GluN2A gene suppression reduces L-DOPA-induced abnormal involuntary movements in parkinsonian rats

L-DOPA-induced dyskinesia (LID) is a common disabling complication of long-term L-DOPA therapy in Parkinson's disease (PD). LID development is associated with maladaptive plasticity mechanisms in striatal circuits contributed by dysregulated dopamine and glutamate signaling. Upregulation of the NMDAR subunit 2A (GluN2A) over chronic L-DOPA treatment is thought to play a role in corticostriatal synaptic changes. We investigated the motor effects of selective GluN2A gene silencing by injecting a shRNA vector in the striatum of hemiparkinsonian rats. Striatal GluN2A knockdown significantly reduced abnormal involuntary movements (AIMs) while sustaining the therapeutic benefit of L-DOPA. These findings suggest that targeted adjustments of striatal NMDAR subunit composition may be a promising strategy for managing the long-term therapy of PD.

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来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).