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Ameliorative effects of a phosphodiesterase 10A inhibitor, MR1916 on L-DOPA-induced dyskinesia in parkinsonian rats.
Pharmacological Reports ( IF 3.6 ) Pub Date : 2020-03-06 , DOI: 10.1007/s43440-020-00060-y
Keita Arakawa 1 , Natsuko Yuge 1 , Shunsuke Maehara 1
Affiliation  

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.

中文翻译:

磷酸二酯酶10A抑制剂MR1916对帕金森病大鼠L-DOPA诱导的运动障碍的改善作用。

背景技术使用L-3,4-二羟基苯丙氨酸(L-DOPA)的多巴胺替代疗法是帕金森氏病(PD)患者的金标准治疗。然而,长期服用L-DOPA会引起过度的不自主运动,称为L-DOPA引起的运动障碍。因此,需要新颖的药理治疗。方法我们研究了磷酸二酯酶10A(PDE10A)抑制剂MR1916和目前可用的抗运动药金刚烷胺在长期服用L-DOPA后单侧6-OHDA病变大鼠表现出稳定的运动障碍的作用。我们还通过单侧6-OHDA损伤大鼠的步进试验研究了MR1916和金刚烷胺对L-DOPA所致前肢运动能力改善的影响。结果MR1916(0.03‒0.3 mg / kg,po)以剂量依赖的方式减少L-DOPA引起的运动障碍,在0.1和0.3 mg / kg的剂量下显示出显着的作用,而金刚烷胺(40 mg / kg,sc)没有明显的作用。MR1916(0.03±0.3 mg / kg,口服)和金刚烷胺(40 mg / kg,皮下注射)均不影响单侧6-OHDA损伤大鼠的L-DOPA诱导的抗帕金森病作用。结论这些结果表明,MR1916特异性减轻L-DOPA引起的运动障碍,而不会影响L-DOPA对帕金森病大鼠的抗帕金森病作用。
更新日期:2020-03-06
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