The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson's Disease.
The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson's Disease.
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DOI：
10.3390/cells9102265
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发表时间：
2020-10-09
期刊：
影响因子：
6
通讯作者：
Steiner H
中科院分区：
文献类型：
--
作者：
Altwal F;Moon C;West AR;Steiner H
左旋多巴（L-DOPA）治疗帕金森氏病受到L-DOPA诱导的运动障碍出现的限制。这种运动障碍与纹状体神经元的异常基因调控有关，这是由5-羟色胺末端的异常多巴胺释放引起的。以前的研究表明，用选择性5-羟色胺再摄取抑制剂（SSRIs）或5-HT 1A受体激动剂调节纹状体5-羟色胺神经支配可以减轻左旋多巴诱导的运动障碍。我们研究了一种新的多巴胺能药物，维拉唑酮，它结合了SSRI和5-HT 1A部分激动剂的特性，对左旋多巴诱导的行为和基因调控的纹状体在帕金森病的动物模型的影响。在通过6-羟基多巴胺（6-OHDA）进行单侧多巴胺耗竭后，大鼠接受单独的L-DOPA（5 mg/kg）或与维拉唑酮（10 mg/kg）组合的重复治疗3周。基因调控，然后绘制整个纹状体使用原位杂交组织化学。维拉唑酮抑制左旋多巴诱导的运动障碍和转向行为的发展，但不干扰左旋多巴的促动力作用（前肢踏步）。L-DOPA治疗显著增加了病变同侧纹状体中强啡肽（直接途径）、5-HT 1B和zif 268 mRNA的表达。这些作用被维拉唑酮抑制。相反，维拉唑酮对脑啡肽表达（间接途径）或完整纹状体中的基因表达没有影响。因此，维拉唑酮抑制左旋多巴诱导的基因调节选择性的多巴胺耗尽纹状体的直接途径，分子变化被认为是关键的左旋多巴诱导的运动障碍。这些发现将维拉唑酮（一种批准的抗抑郁药）定位为治疗左旋多巴诱导的运动副作用的潜在辅助药物。
Levodopa (L-DOPA) treatment in Parkinson’s disease is limited by the emergence of L-DOPA-induced dyskinesia. Such dyskinesia is associated with aberrant gene regulation in neurons of the striatum, which is caused by abnormal dopamine release from serotonin terminals. Previous work showed that modulating the striatal serotonin innervation with selective serotonin reuptake inhibitors (SSRIs) or 5-HT1A receptor agonists could attenuate L-DOPA-induced dyskinesia. We investigated the effects of a novel serotonergic agent, vilazodone, which combines SSRI and 5-HT1A partial agonist properties, on L-DOPA-induced behavior and gene regulation in the striatum in an animal model of Parkinson’s disease. After unilateral dopamine depletion by 6-hydroxydopamine (6-OHDA), rats received repeated L-DOPA treatment (5 mg/kg) alone or in combination with vilazodone (10 mg/kg) for 3 weeks. Gene regulation was then mapped throughout the striatum using in situ hybridization histochemistry. Vilazodone suppressed the development of L-DOPA-induced dyskinesia and turning behavior but did not interfere with the prokinetic effects of L-DOPA (forelimb stepping). L-DOPA treatment drastically increased the expression of dynorphin (direct pathway), 5-HT1B, and zif268 mRNA in the striatum ipsilateral to the lesion. These effects were inhibited by vilazodone. In contrast, vilazodone had no effect on enkephalin expression (indirect pathway) or on gene expression in the intact striatum. Thus, vilazodone inhibited L-DOPA-induced gene regulation selectively in the direct pathway of the dopamine-depleted striatum, molecular changes that are considered critical for L-DOPA-induced dyskinesia. These findings position vilazodone, an approved antidepressant, as a potential adjunct medication for the treatment of L-DOPA-induced motor side effects.
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长时间选择性5-羟色胺再摄取抑制对Hemi-Parkinsonian大鼠L- dopa诱导的运动障碍的发育和表达的影响。
影响因子：
4.7
作者：
Conti MM;Ostock CY;Lindenbach D;Goldenberg AA;Kampton E;Dell'isola R;Katzman AC;Bishop C
通讯作者：
Bishop C
影响因子：
2.9
作者：
ABERCROMBIE, ED;BONATZ, AE;ZIGMOND, MJ
通讯作者：
ZIGMOND, MJ
影响因子：
2.5
作者：
ARAI, R;KARASAWA, N;NAGATSU, I
通讯作者：
NAGATSU, I
影响因子：
--
作者：
Cenci, M. Angela;Konradi, Christine
通讯作者：
Konradi, Christine
影响因子：
3.5
作者：
Cenci, MA
通讯作者：
Cenci, MA