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磷酸二酯酶 10A 抑制剂 MR1916 对帕金森病大鼠左旋多巴诱导运动障碍的改善作用。

Ameliorative effects of a phosphodiesterase 10A inhibitor, MR1916 on L-DOPA-induced dyskinesia in parkinsonian rats.

机构信息

Biology Laboratory, Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba, Shizuoka, 412-8524, Japan.

出版信息

Pharmacol Rep. 2020 Apr;72(2):443-448. doi: 10.1007/s43440-020-00060-y. Epub 2020 Mar 6.

DOI:10.1007/s43440-020-00060-y

PMID:32144743

Abstract

BACKGROUND

Dopamine replacement therapy using L-3,4-dihydroxyphenylalanine (L-DOPA) is a gold standard treatment in patients with Parkinson's disease (PD); however, chronic administration of L-DOPA causes excessive involuntary movements called L-DOPA-induced dyskinesia. Therefore, the novel pharmacological treatment is needed.

METHODS

We examined the antidyskinetic effect of a phosphodiesterase 10A (PDE10A) inhibitor, MR1916 and a currently available antidyskinetic drug, amantadine in unilateral 6-OHDA lesioned rats exhibited stably dyskinesia after chronic administration of L-DOPA. We also examined the influence of MR1916 and amantadine on the improvement of forelimb akinesia induced by L-DOPA using stepping test in unilateral 6-OHDA lesioned rats.

RESULTS

MR1916 (0.03‒0.3 mg/kg, po) reduced L-DOPA-induced dyskinesia in a dose-dependent manner and showed significant effects at doses of 0.1 and 0.3 mg/kg, while amantadine (40 mg/kg, sc) had no remarkable effects. Neither MR1916 (0.03‒0.3 mg/kg, po) nor amantadine (40 mg/kg, sc) affected the antiparkinsonian effects induced by L-DOPA in unilateral 6-OHDA lesioned rats.

CONCLUSIONS

These results indicate that MR1916 specifically reduces L-DOPA-induced dyskinesia without affecting the antiparkinsonian effect of L-DOPA in parkinsonian rats.

摘要

背景

使用 L-3,4-二羟基苯丙氨酸（L-DOPA）进行多巴胺替代疗法是帕金森病（PD）患者的金标准治疗方法；然而，L-DOPA 的慢性给药会导致称为 L-DOPA 诱导的运动障碍的过度不自主运动。因此，需要新的药理学治疗方法。

方法

我们研究了磷酸二酯酶 10A（PDE10A）抑制剂 MR1916 和现有的抗运动障碍药物金刚烷胺对单侧 6-OHDA 损伤大鼠在慢性 L-DOPA 给药后表现出稳定运动障碍的抗运动障碍作用。我们还研究了 MR1916 和金刚烷胺对单侧 6-OHDA 损伤大鼠 L-DOPA 诱导的前肢运动不能改善的影响，使用步测试验。

结果

MR1916（0.03-0.3mg/kg，po）以剂量依赖性方式减少 L-DOPA 诱导的运动障碍，并且在 0.1 和 0.3mg/kg 的剂量下显示出显著效果，而金刚烷胺（40mg/kg，sc）没有显著效果。MR1916（0.03-0.3mg/kg，po）和金刚烷胺（40mg/kg，sc）均不影响单侧 6-OHDA 损伤大鼠中 L-DOPA 诱导的抗帕金森作用。