Cell Biology and Toxicology

, Volume 29, Issue 5, pp 339–353

Platinum drugs and neurotoxicity: effects on intracellular calcium homeostasis

  • Valeria Maria Piccolini
  • Maria Grazia Bottone
  • Giovanni Bottiroli
  • Sandra Angelica De Pascali
  • Francesco Paolo Fanizzi
  • Graziella Bernocchi
Original Research

Abstract

[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.

Keywords

Calcium homeostasis Cisplatin analogs CNS development Immunocytochemistry Neurotoxicity 

Abbreviations

[Ca2+]i

Intracellular calcium concentration

CA

Cornu Ammonis

CB

Calbindin

cisPt

Cisplatin

DG

Dentate gyrus

gl

Granule layer

hi

Hilus

l/ml

Lacunosum–moleculare layer

ml

Molecular layer

OD

Optical density

PD

Postnatal day

Pl

Pyramidal layer

PMCA1

Plasma membrane calcium ATPase1

PtAcacDMS

[Pt(O,O′-acac)(γ-acac)(DMS)]

rl

Radiatum layer

SD

Standard deviation

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Valeria Maria Piccolini
    • 1
  • Maria Grazia Bottone
    • 1
    • 2
  • Giovanni Bottiroli
    • 2
  • Sandra Angelica De Pascali
    • 3
  • Francesco Paolo Fanizzi
    • 3
  • Graziella Bernocchi
    • 1
  1. 1.Dipartimento di Biologia e Biotecnologie “L. Spallanzani” Università di PaviaPaviaItaly
  2. 2.Sezione di Istochimica e CitometriaIstituto di Genetica Molecolare del CNRPaviaItaly
  3. 3.Dipartimento di Scienze e Tecnologie Biologiche ed AmbientaliUniversità del SalentoLecceItaly

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