多巴胺激动剂共处理改变左旋多巴诱导的运动障碍的神经可塑性和药理学。
Dopamine Agonist Cotreatment Alters Neuroplasticity and Pharmacology of Levodopa-Induced Dyskinesia.
机构信息
Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
Department of Neurology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
出版信息
Mov Disord. 2023 Mar;38(3):410-422. doi: 10.1002/mds.29301. Epub 2023 Jan 19.
BACKGROUND
Current models of levodopa (L-dopa)-induced dyskinesia (LID) are obtained by treating dopamine-depleted animals with L-dopa. However, patients with LID receive combination therapies that often include dopamine agonists.
OBJECTIVE
Using 6-hydroxydopamine-lesioned rats as a model, we aimed to establish whether an adjunct treatment with the D2/3 agonist ropinirole impacts on patterns of LID-related neuroplasticity and drug responses.
METHODS
Different regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment were compared using measures of hypokinesia and dyskinesia. Striatal expression of ∆FosB and angiogenesis markers were studied immunohistochemically. Antidyskinetic effects of different drug categories were investigated in parallel groups of rats receiving either L-dopa monotreatment or L-dopa combined with ropinirole.
RESULTS
We defined chronic regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment inducing overall similar abnormal involuntary movement scores. Compared with the monotreatment group, animals receiving the L-dopa-ropinirole combination exhibited an overall lower striatal expression of ∆FosB with a distinctive compartmental distribution. The expression of angiogenesis markers and blood-brain barrier hyperpermeability was markedly reduced after L-dopa-ropinirole cotreatment compared with L-dopa monotreatment. Moreover, significant group differences were detected upon examining the response to candidate antidyskinetic drugs. In particular, compounds modulating D1 receptor signaling had a stronger effect in the L-dopa-only group, whereas both amantadine and the selective NMDA antagonist MK801 produced a markedly larger antidyskinetic effect in L-dopa-ropinirole cotreated animals.
CONCLUSIONS
Cotreatment with ropinirole altered LID-related neuroplasticity and pharmacological response profiles. The impact of adjuvant dopamine agonist treatment should be taken into consideration when investigating LID mechanisms and candidate interventions in both clinical and experimental settings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
背景
目前的左旋多巴（L-dopa）诱导运动障碍（LID）模型是通过用 L-dopa 治疗多巴胺耗竭动物获得的。然而，患有 LID 的患者接受的联合治疗通常包括多巴胺激动剂。
目的
我们使用 6-羟多巴胺损伤大鼠作为模型，旨在确定辅助治疗 D2/3 激动剂罗匹尼罗是否会影响 LID 相关神经可塑性和药物反应模式。
方法
使用运动减少和运动障碍的测量值，比较 L-dopa 单一治疗和 L-dopa-ropinirole 联合治疗的不同方案。使用免疫组织化学研究纹状体中 ∆FosB 和血管生成标记物的表达。在接受 L-dopa 单一治疗或 L-dopa 与罗匹尼罗联合治疗的大鼠的平行组中，研究了不同药物类别的抗运动障碍作用。
结果
我们确定了慢性 L-dopa 单一治疗和 L-dopa-ropinirole 联合治疗方案，诱导总体相似的异常不自主运动评分。与单一治疗组相比，接受 L-dopa-ropinirole 联合治疗的动物表现出总体较低的纹状体 ∆FosB 表达，具有独特的隔室分布。与 L-dopa 单一治疗相比，L-dopa-ropinirole 联合治疗后血管生成标记物和血脑屏障通透性明显降低。此外，在检查候选抗运动障碍药物的反应时，检测到显著的组间差异。特别是，调节 D1 受体信号的化合物在仅接受 L-dopa 的组中具有更强的作用，而金刚烷胺和选择性 NMDA 拮抗剂 MK801 在接受 L-dopa-ropinirole 联合治疗的动物中产生了明显更大的抗运动障碍作用。
结论
罗匹尼罗联合治疗改变了 LID 相关的神经可塑性和药物反应谱。在临床和实验环境中研究 LID 机制和候选干预措施时，应考虑辅助多巴胺激动剂治疗的影响。
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