Zanetti Lucia, Török Ferenc, Leitzbach Luisa, Stark Holger, Striessnig Jörg
Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Duesseldorf, Germany.
Channels (Austin). 2025 Dec;19(1):2556101. doi: 10.1080/19336950.2025.2556101. Epub 2025 Sep 16.
A growing body of preclinical evidence indicates that the inhibition of voltage-gated Cav1.3 L-type Ca channels could be a therapeutic concept for the therapy of treatment-resistant hypertension, spinal injury and for neuroprotection in early Parkinson's disease (PD). However, available Ca-channel blockers are potent inhibitors of vascular Cav1.2 L-type channels which can cause low blood pressure as an adverse drug reaction. Therefore, Cav1.3-selective inhibitors are needed to further investigate the therapeutic potential of Cav1.3 as drug target in vivo. The bicyclic diterpene alcohol sclareol has recently been reported to exert neuroprotective properties in a mouse PD model by blocking Cav1.3 L-type channels. This study investigates the proposed Cav1.3-selectivity of sclareol compared to Cav1.2 and to other voltage-gated Ca channels in whole-cell patch-clamp experiments. Various stimulation protocols, including dopamine neuron-like firing patterns show that sclareol is neither a subtype-selective nor a potent blocker of heterologously expressed Cav1.3 and inhibits also Cav2.3 channels. Therefore, the contribution of Cav1.3 channel inhibition for the previously reported neuroprotective effects of sclareol in a mouse PD model remains unclear. In addition, cinnarizine, a vertigo therapeutic also under investigation for inhibition of Cav1.3-mediated aldosterone-secretion, inhibits Cav1.3 channels in a frequency-dependent manner, but also without relevant selectivity with respect to Cav1.3.
越来越多的临床前证据表明，抑制电压门控的Cav1.3 L型钙通道可能是治疗难治性高血压、脊髓损伤以及早期帕金森病（PD）神经保护的一种治疗理念。然而，现有的钙通道阻滞剂是血管Cav1.2 L型通道的强效抑制剂，可导致低血压这一药物不良反应。因此，需要Cav1.3选择性抑制剂来进一步研究Cav1.3作为体内药物靶点的治疗潜力。双环二萜醇香紫苏醇最近被报道通过阻断Cav1.3 L型通道在小鼠PD模型中发挥神经保护作用。本研究在全细胞膜片钳实验中研究了香紫苏醇相对于Cav1.2和其他电压门控钙通道所提出的Cav1.3选择性。各种刺激方案，包括多巴胺神经元样放电模式表明，香紫苏醇既不是异源表达的Cav1.3的亚型选择性抑制剂，也不是强效阻滞剂，并且还抑制Cav2.3通道。因此，Cav1.3通道抑制对香紫苏醇先前在小鼠PD模型中报道的神经保护作用的贡献仍不清楚。此外，桂利嗪是一种正在研究用于抑制Cav1.3介导的醛固酮分泌的眩晕治疗药物，它以频率依赖性方式抑制Cav1.3通道，但对Cav1.3也没有相关的选择性。
