Institute for Ophthalmic Research, University of Tübingen, 72076, Tübingen, Germany.
Institute of Physiology II, University Hospital Jena, Friedrich Schiller University Jena, 07743, Jena, Germany.
Cell Death Dis. 2022 Jan 10;13(1):47. doi: 10.1038/s41419-021-04482-1.
Hereditary degeneration of photoreceptors has been linked to over-activation of Ca-permeable channels, excessive Ca-influx, and downstream activation of Ca-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca-influx, most probably by blocking the pore of Ca-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca-independent degenerative mechanisms.
感光细胞的遗传性退化与钙通透性通道的过度激活、钙离子内流过多以及钙依赖性钙蛋白酶型蛋白酶的下游激活有关。不幸的是，经过 20 多年的相关研究，仍然缺乏确凿的证据证明钙通道阻滞剂能显著且可重复地保护感光细胞。在这里，我们表明，抗高血压药物地尔硫卓的 D-和 L-顺式对映体都非常有效地阻止感光细胞钙离子内流，很可能是通过阻断钙通透性通道的孔来实现的。然而，出人意料的是，这种阻断既没有降低钙蛋白酶型蛋白酶的活性，也没有导致感光细胞的保护。值得注意的是，地尔硫卓的 L-顺式对映体的应用甚至导致感光细胞死亡的强烈增加。这些发现对以前提出的钙与视网膜变性之间的联系提出了质疑，并且对未来的治疗发展具有高度的相关性，因为它们可能有助于将研究重点重新聚焦于替代的、与钙无关的退行性机制上。
