Protective effect of T-type calcium channel blocker flunarizine on cisplatin-induced death of auditory cells

Hong Seob So, Channy Park, Hyung Jin Kim, Jung Han Lee, Sung Yeol Park, Jai Hyung Lee, Zee Won Lee, Hyung Min Kim, Federico Kalinec, David J. Lim, Raekil Park

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Changes in intracellular Ca2+ level are involved in a number of intracellular events, including triggering of apoptosis. The role of intracellular calcium mobilization in cisplatin-induced hair cell death, however, is still unknown. In this study, the effect of calcium channel blocker flunarizine (Sibelium™), which is used to prescribe for vertigo and tinnitus, on cisplatin-induced hair cell death was investigated in a cochlear organ of Corti-derived cell line, HEI-OC1, and the neonatal (P2) rat organ of Corti explant. Cisplatin induced apoptotic cell death showing nuclear fragmentation, DNA ladder, and TUNEL positive in both HEI-OC1 and primary organ of Corti explant. Flunarizine significantly inhibited the cisplatin-induced apoptosis. Unexpectedly, flunarizine increased the intracellular calcium ([Ca2+]i) levels of HEI-OC1. However, the protective effect of flunarizine against cisplatin was not mediated by modulation of intracellular calcium level. Treatment of cisplatin resulted in ROS generation and lipid peroxidation in HEI-OC1. Flunarizine did not attenuate ROS production but inhibited lipid peroxidation and mitochondrial permeability transition in cisplatin-treated cells. This result suggests that the protective mechanism of flunarizine on cisplatin-induced cytotoxicity is associated with direct inhibition of lipid peroxidation and mitochondrial permeability transition.

Original languageEnglish (US)
Pages (from-to)127-139
Number of pages13
JournalHearing Research
Volume204
Issue number1-2
DOIs
StatePublished - Jun 2005

Keywords

  • Cisplatin
  • Flunarizine
  • Organ of Corti
  • Ototoxicity

ASJC Scopus subject areas

  • Sensory Systems

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