Instituto Fundación Teófilo Hernando, Madrid, Spain.
Instituto Fundación Teófilo Hernando, Madrid, Spain; Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid, Madrid, Spain.
Cell Calcium. 2024 Nov;123:102928. doi: 10.1016/j.ceca.2024.102928. Epub 2024 Jul 6.
As the uncontrolled entry of calcium ions (Ca) through plasmalemmal calcium channels is a cell death trigger, the conjecture is here raised that mitigating such an excess of Ca entry should rescue from death the vulnerable neurons in neurodegenerative diseases (NDDs). However, this supposition has failed in some clinical trials (CTs). Thus, a recent CT tested whether isradipine, a blocker of the Cav1 subtype of voltage-operated calcium channels (VOCCs), exerted a benefit in patients with Parkinson's disease (PD); however, outcomes were negative. This is one more of the hundreds of CTs done under the principle of one-drug-one-target, that have failed in Alzheimer's disease (AD) and other NDDs during the last three decades. As there are myriad calcium channels to let Ca ions gain the cell cytosol, it seems reasonable to predict that blockade of Ca entry through a single channel may not be capable of preventing the Ca flood of cells by the uncontrolled Ca entry. Furthermore, as Ca signaling is involved in the regulation of myriad functions in different cell types, it seems also reasonable to guess that a therapy should be more efficient by targeting different cells with various drugs. Here, we propose to mitigate Ca entry by the simultaneous partial blockade of three quite different subtypes of plasmalemmal calcium channels that is, the Cav1 subtype of VOCCs, the Orai1 store-operated calcium channel (SOCC), and the purinergic P2X7 calcium channel. All three channels are expressed in both microglia and neurons. Thus, by targeting the three channels with a combination of three drug blockers we expect favorable changes in some of the pathogenic features of NDDs, namely (i) to mitigate Ca entry into microglia; (ii) to decrease the Ca-dependent microglia activation; (iii) to decrease the sustained neuroinflammation; (iv) to decrease the uncontrolled Ca entry into neurons; (v) to rescue vulnerable neurons from death; and (vi) to delay disease progression. In this review we discuss the arguments underlying our triad hypothesis in the sense that the combination of three repositioned medicines targeting Cav1, Orai1, and P2X7 calcium channels could boost neuroprotection and delay the progression of AD and other NDDs.
由于钙离子（Ca）通过质膜钙通道的不受控制的进入是细胞死亡的触发因素，因此这里提出的假设是，减轻这种过量的 Ca 进入应该可以挽救神经退行性疾病（NDD）中脆弱的神经元。然而，这一假设在一些临床试验（CTs）中失败了。因此，最近的一项 CT 测试了维拉帕米（一种电压门控钙通道（VOCC）Cav1 亚型的阻滞剂）是否对帕金森病（PD）患者有益；然而，结果是负面的。这是在过去三十年中，在一种药物一种靶点的原则下进行的数百项 CT 之一，在阿尔茨海默病（AD）和其他 NDD 中均以失败告终。由于有无数的钙通道可以让钙离子进入细胞质，因此可以合理地预测，通过单一通道阻断 Ca 进入可能不足以防止不受控制的 Ca 进入导致细胞内 Ca 泛滥。此外，由于 Ca 信号参与不同细胞类型的多种功能的调节，因此也可以合理地猜测，通过针对不同细胞使用各种药物进行治疗，疗效会更高。在这里，我们建议通过同时部分阻断三种截然不同的质膜钙通道来减轻 Ca 进入，即 VOCC 的 Cav1 亚型、Orai1 储存操纵钙通道（SOCC）和嘌呤能 P2X7 钙通道。这三种通道都在小胶质细胞和神经元中表达。因此，通过使用三种药物阻滞剂的组合靶向这三种通道，我们预计会对 NDD 的一些致病特征产生有利的变化，即：（i）减轻 Ca 进入小胶质细胞；（ii）减少 Ca 依赖性小胶质细胞激活；（iii）减少持续的神经炎症；（iv）减少 Ca 进入神经元的不受控制的进入；（v）挽救脆弱神经元免于死亡；（vi）延迟疾病进展。在这篇综述中，我们讨论了我们三元假说的基本原理，即通过组合三种针对 Cav1、Orai1 和 P2X7 钙通道的再定位药物，可以增强神经保护作用并延缓 AD 和其他 NDD 的进展。
