Institut für Angewandte Physiologie, Universität Ulm, 89081 Ulm, Germany; email:
Abteilung Pharmakologie und Toxikologie, Institut für Pharmazie, and Center for Molecular Biosciences Innsbruck, Universität Innsbruck, A-6020 Innsbruck, Austria; email:
Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:263-289. doi: 10.1146/annurev-pharmtox-010818-021214.
The motor symptoms of Parkinson's disease (PD) mainly arise from degeneration of dopamine neurons within the substantia nigra. As no disease-modifying PD therapies are available, and side effects limit long-term benefits of current symptomatic therapies, novel treatment approaches are needed. The ongoing phase III clinical study STEADY-PD is investigating the potential of the dihydropyridine isradipine, an L-type Ca channel (LTCC) blocker, for neuroprotective PD therapy. Here we review the clinical and preclinical rationale for this trial and discuss potential reasons for the ambiguous outcomes of in vivo animal model studies that address PD-protective dihydropyridine effects. We summarize current views about the roles of Cav1.2 and Cav1.3 LTCC isoforms for substantia nigra neuron function, and their high vulnerability to degenerative stressors, and for PD pathophysiology. We discuss different dihydropyridine sensitivities of LTCC isoforms in view of their potential as drug targets for PD neuroprotection, and we conclude by considering how these aspects could guide further drug development.
帕金森病（PD）的运动症状主要源于黑质内多巴胺神经元的退化。由于目前尚无改变疾病进程的 PD 治疗方法，且当前对症治疗的长期疗效受到副作用的限制，因此需要新的治疗方法。正在进行的 III 期临床试验 STEADY-PD 正在研究二氢吡啶类药物异搏定（一种 L 型钙通道（LTCC）阻断剂）在神经保护性 PD 治疗中的潜力。本文综述了该试验的临床前和临床理论基础，并讨论了体内动物模型研究中 PD 保护作用的二氢吡啶效应结果存在差异的潜在原因。我们总结了目前关于 Cav1.2 和 Cav1.3 LTCC 同工型在黑质神经元功能及其对退行性应激的高度易感性，以及它们在 PD 病理生理学中的作用的观点。我们考虑了 LTCC 同工型的不同二氢吡啶敏感性，以及它们作为 PD 神经保护药物靶点的潜力，并在最后得出结论，认为这些方面可以为进一步的药物开发提供指导。
