Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
Research Center, Mochida Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
Mov Disord. 2018 May;33(5):805-814. doi: 10.1002/mds.27341. Epub 2018 Mar 6.
Phosphodiesterase 10A is a member of the phosphodiesterase family whose brain expression is restricted to the striatum. Phosphodiesterase 10A regulates cyclic adenosine monophosphate and cyclic guanosine monophosphate, which mediate responses to dopamine receptor activation, and the levels of these cyclic nucleotides are decreased in experimental models of l-dopa-induced dyskinesia. The elevation of cyclic adenosine monophosphate/cyclic guanosine monophosphate levels by phosphodiesterase 10A inhibition may thus be targeted to reduce l-dopa-induced dyskinesia.
The present study was aimed at determining the potential antidyskinetic effects of phosphodiesterase 10A inhibitors in a primate model of Parkinson's disease (PD). The experiments performed in this model were also intended to provide translational data for the design of future clinical trials.
Five MPTP-treated macaques with advanced parkinsonism and reproducible l-dopa-induced dyskinesia were used. MR1916, a selective phosphodiesterase 10A inhibitor, at doses 0.0015 to 0.05 mg/kg, subcutaneously, or its vehicle (control test) was coadministered with l-dopa methyl ester acutely (predetermined optimal and suboptimal subcutaneous doses) and oral l-dopa chronically as daily treatment for 5 weeks. Standardized scales were used to assess motor disability and l-dopa-induced dyskinesia by blinded examiners. Pharmacokinetics was also examined.
MR1916 consistently reduced l-dopa-induced dyskinesia in acute tests of l-dopa optimal and suboptimal doses. Significant effects were present with every MR1916 dose tested, but the most effective was 0.015 mg/kg. None of the MR1916 doses tested affected the antiparkinsonian action of l-dopa at the optimal dose. The anti-l-dopa-induced dyskinesia effect of MR1916 (0.015 mg/kg, subcutaneously) was sustained with chronic administration, indicating that tolerance did not develop over the 5-week treatment. No adverse effects were observed after MR1916 administration acutely or chronically.
Results show that regulation of striatal cyclic nucleotides by phosphodiesterase 10A inhibition could be a useful therapeutic approach for l-dopa-induced dyskinesia, and therefore data support further studies of selective phosphodiesterase 10A inhibitors for PD therapy. © 2018 International Parkinson and Movement Disorder Society.
磷酸二酯酶 10A 是磷酸二酯酶家族的一员，其脑表达仅限于纹状体。磷酸二酯酶 10A 调节环腺苷酸和环鸟苷酸，这两种物质介导多巴胺受体激活的反应，而在左旋多巴诱导运动障碍的实验模型中，这些环核苷酸的水平降低。通过抑制磷酸二酯酶 10A 升高环腺苷酸/环鸟苷酸水平，可能有助于减少左旋多巴诱导的运动障碍。
本研究旨在确定磷酸二酯酶 10A 抑制剂在灵长类帕金森病（PD）模型中的潜在抗运动障碍作用。在该模型中进行的实验还旨在为未来临床试验的设计提供转化数据。
使用 5 只接受 MPTP 治疗的、患有晚期帕金森病和可重现性左旋多巴诱导运动障碍的猕猴。皮下给予磷酸二酯酶 10A 选择性抑制剂 MR1916，剂量为 0.0015 至 0.05mg/kg，或其载体（对照试验），与左旋多巴甲酯急性共给药（预先确定的最佳和亚最佳皮下剂量），并作为每日治疗，持续 5 周。由盲法检查者使用标准化量表评估运动障碍和左旋多巴诱导的运动障碍。还检查了药代动力学。
MR1916 一致降低了急性左旋多巴最佳和亚最佳剂量测试中的左旋多巴诱导的运动障碍。在测试的每一个 MR1916 剂量下均有显著作用，但最有效的剂量为 0.015mg/kg。测试的 MR1916 剂量均未影响最佳剂量下左旋多巴的抗帕金森病作用。MR1916（皮下 0.015mg/kg）的抗左旋多巴诱导运动障碍作用在慢性给药时持续存在，表明在 5 周的治疗过程中未产生耐受性。MR1916 急性或慢性给药后均未观察到不良反应。
结果表明，通过抑制磷酸二酯酶 10A 调节纹状体环核苷酸可能是治疗左旋多巴诱导运动障碍的一种有用的治疗方法，因此数据支持进一步研究选择性磷酸二酯酶 10A 抑制剂治疗 PD。
