Galvan Adriana, Devergnas Annaelle, Pittard Damien, Masilamoni Gunasingh, Vuong Jocelyn, Daniels J Scott, Morrison Ryan D, Lindsley Craig W, Wichmann Thomas
Department of Pharmacology and Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
ACS Chem Neurosci. 2016 Nov 16;7(11):1543-1551. doi: 10.1021/acschemneuro.6b00186. Epub 2016 Sep 20.
Dopaminergic medications ameliorate many of the motor impairments of Parkinson's disease (PD). However, parkinsonism is often only partially reversed by these drugs, and they can have significant side effects. Therefore, a need remains for novel treatments of parkinsonism. Studies in rodents and preliminary clinical evidence have shown that T-type calcium channel (TTCC) antagonists have antiparkinsonian effects. However, most of the available studies utilized nonselective agents. We now evaluated whether systemic injections of the specific TTCC blocker ML218 have antiparkinsonian effects in MPTP-treated parkinsonian Rhesus monkeys. The animals were treated chronically with MPTP until they reached stable parkinsonism. In pharmacokinetic studies, we found that ML218 reaches a peak CSF concentration 1-2 h after s.c. administration. In electrocardiographic studies, we found no effects of ML218 on cardiac rhythmicity. As expected, systemic injections of the dopamine precursor L-DOPA dose-dependently increased the movements in our parkinsonian animals. We then tested the behavioral effects of systemic injections of ML218 (1, 10, or 30 mg/kg) or its vehicle, but did not detect specific antiparkinsonian effects. ML218 (3 or 10 mg/kg) was also not synergistic with L-DOPA. Using recordings of electrocorticogram signals (in one animal), we found that ML218 increased sleep. We conclude that ML218 does not have antiparkinsonian effects in MPTP-treated parkinsonian monkeys, due at least in part, to the agent's sedative effects.
多巴胺能药物可改善帕金森病（PD）的许多运动障碍。然而，帕金森症通常只能被这些药物部分逆转，并且它们可能有显著的副作用。因此，对帕金森症的新治疗方法仍有需求。在啮齿动物中的研究和初步临床证据表明，T型钙通道（TTCC）拮抗剂具有抗帕金森病作用。然而，大多数现有研究使用的是非选择性药物。我们现在评估了全身注射特异性TTCC阻滞剂ML218对经MPTP处理的帕金森病恒河猴是否具有抗帕金森病作用。这些动物长期接受MPTP治疗，直到出现稳定的帕金森症。在药代动力学研究中，我们发现皮下注射后1-2小时ML218的脑脊液浓度达到峰值。在心电图研究中，我们发现ML218对心脏节律没有影响。正如预期的那样，全身注射多巴胺前体左旋多巴可使我们的帕金森病动物的运动呈剂量依赖性增加。然后，我们测试了全身注射ML218（1、10或30mg/kg）或其赋形剂的行为效应，但未检测到特异性抗帕金森病作用。ML218（3或10mg/kg）与左旋多巴也没有协同作用。通过记录脑电图信号（在一只动物中），我们发现ML218增加了睡眠。我们得出结论，ML218对经MPTP处理的帕金森病猴子没有抗帕金森病作用，至少部分原因是该药物的镇静作用。
