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 Ca2+ 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.

中文翻译：

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L 型钙通道作为帕金森病神经保护治疗药物靶点的潜力。

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。由于没有改善疾病的 PD 疗法可用，并且副作用限制了当前对症疗法的长期益处，因此需要新的治疗方法。正在进行的 III 期临床研究 STEADY-PD 正在研究二氢吡啶伊拉地平（一种 L 型 Ca2+ 通道（LTCC）阻滞剂）用于神经保护性 PD 治疗的潜力。在这里，我们回顾了该试验的临床和临床前基本原理，并讨论了解决 PD 保护性二氢吡啶效应的体内动物模型研究结果不明确的潜在原因。我们总结了当前关于 Cav1.2 和 Cav1.3 LTCC 亚型对黑质神经元功能作用的观点，以及它们对退行性压力源和 PD 病理生理学的高度脆弱性。我们讨论了 LTCC 同种型的不同二氢吡啶敏感性，因为它们具有作为 PD 神经保护药物靶点的潜力，最后我们考虑了这些方面如何指导进一步的药物开发。