Dipartimento di Biologia e Biotecnologie "L. Spallanzani" Università di Pavia, via Ferrata 9, 27100, Pavia, Italy.
Cell Biol Toxicol. 2013 Oct;29(5):339-53. doi: 10.1007/s10565-013-9252-3. Epub 2013 Aug 28.
[Pt(O,O'-acac)(γ-acac)(DMS)] (PtAcacDMS) is a new platinum compound showing low reactivity with nucleobases and specific reactivity with sulfur ligands intracellularly. It induces apoptosis in breast cancer cells, but appears to be less neurotoxic to the developing cerebellum than cisplatin (cisPt). The aim of this study was to assess the neurotoxicity of platinum compounds on calcium homeostasis in the dentate gyrus and Cornu Ammonis regions of the hippocampal formation during rat postnatal development. Two intracellular calcium homeostasis systems were taken for measurement, calbindin, a calcium buffer protein, and a plasma membrane calcium ATPase (PMCA1). The platinum compounds showed different effects on these markers in the two areas. One day after injection (PD11), cisPt decreased calbindin immunoreactivity and PMCA1 labeling in both regions; at PD17, the downregulation of PMCA1 persisted. Instead, PtAcacDMS produced varying effects on calbindin immunoreactivity in the two regions at PD11 and PD17; but in all cases, the changes incurred in calbindin immunoreactivity were counterbalanced by changes produced in PMCA1 expression. In conclusion, PtAcacDMS seems to affect calcium homeostasis in the central nervous system differently than cisPt. Both the platinum compounds act early to alter the calbindin buffering system. However, the most important difference between cisPt and PtAcacDMS is that, in vivo, the latter acts early to stimulate calcium efflux from nerve cells as reflected by its effect on PMCA1. The rapid onset of an activated calcium pump appears to be essential to cope with the excessive intracellular calcium concentration stemming from the downregulation of calbindin which could damage neuron function and morphology.
[Pt(O,O'-acac)(γ-acac)(DMS)]（PtAcacDMS）是一种新的铂化合物，与核碱基反应性低，而与细胞内硫配体反应性强。它能诱导乳腺癌细胞凋亡，但对发育中的小脑的神经毒性似乎低于顺铂（cisPt）。本研究旨在评估铂化合物对钙稳态的神经毒性，以了解钙稳态在大鼠出生后发育过程中海马结构齿状回和 Cornu Ammonis 区的变化。本研究检测了两种细胞内钙稳态系统，钙结合蛋白 calbindin 和质膜钙 ATP 酶（PMCA1）。铂化合物在这两个区域对这些标志物有不同的影响。在注射后 1 天（PD11），cisPt 降低了两个区域的 calbindin 免疫反应性和 PMCA1 标记；在 PD17，PMCA1 的下调仍然存在。相反，PtAcacDMS 在 PD11 和 PD17 时对两个区域的 calbindin 免疫反应性产生不同的影响；但在所有情况下，calbindin 免疫反应性的变化都被 PMCA1 表达的变化所抵消。总之，PtAcacDMS 似乎对中枢神经系统的钙稳态的影响与 cisPt 不同。两种铂化合物都能早期作用于改变 calbindin 缓冲系统。然而，cisPt 和 PtAcacDMS 之间最重要的区别是，在体内，后者早期通过其对 PMCA1 的作用来刺激神经细胞的钙外流。快速激活钙泵似乎对于应对源自 calbindin 下调的过多细胞内钙浓度至关重要，因为这可能会损害神经元功能和形态。
