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

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

doi:10.1016/j.heares.2005.01.011

Cited by 66 publications

(68 citation statements)

References 51 publications

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“…In our previous study, we demonstrated that another T-type calcium channel blocker, pimozide, also showed the cytoprotetive effect against cisplatin-mediated HEI-OC1 auditory cell deaths. 14 We, therefore, verified the effects of other calcium channel brokers, including nicardipine, nifedipine, diltiazem, flunarizine and pimozide, on HO-1 induction by Western blot. As shown in Figure 7e, both pimozide and flunarizine could markedly induce HO-1 proteins in HEI-OC1 cells.…”

Section: Flunarizine Dramatically Increased the Nuclear Translocationsupporting

confidence: 54%

“…26,27 Recently, we reported that flunarizine, an antagonist of T-type specific calcium channels CACNa1G and CACNa1I, protects auditory cells from cisplatin through inhibition of lipid peroxidation and mitochondrial dysfunction. 14 In the present study, we have further elucidated that Nrf2/HO-1 signaling is directly involved in the protective effect of flunarizine against cisplatin in both HEI-OC auditory cells and in the primary rat P(2) organ of Corti explants.…”

Section: Discussionmentioning

confidence: 59%

“…Our previous data demonstrated that both flunarizine and cisplatin increase [Ca 2 þ ] i in auditory cells, 14 Furthermore, an intracellular Ca 2 þ chelator, BAPTA-AM, and a calcium ionophore, A23187, did not affect the cytotoxicity of cisplatin as well as the protective effect of flunarizine.…”

Section: Discussionmentioning

confidence: 90%

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Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Kim

et al. 2006

Cell Death Differ

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We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GSTl-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.

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Section: Flunarizine Dramatically Increased the Nuclear Translocationsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 59%

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Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Kim

et al. 2006

Cell Death Differ

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“…It is one of the most common solvents for dissolving hydrophobic compounds employed in vivo or in vitro studies. DMSO has frequently been used in studies of the inner ear; however, its potential side effects are unknown and have been largely overlooked in previous studies (Basile et al, 1996;Guitton et al, 2003;Harris et al, 2005;Lee et al, 2002;So et al, 2005). Our in vitro results obtained with postnatal cochlear cultures showed little or no evidence of hair cell damage following 24 h treatment with 0.25% DMSO or less.…”

Section: Discussionmentioning

confidence: 54%

Cytotoxic effects of dimethyl sulphoxide (DMSO) on cochlear organotypic cultures

2008

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The amphipathic molecule dimethyl sulphoxide (DMSO) is a solvent often used to dissolve compounds applied to the inner ear; however, little is known about its potential cytotoxic side effects. To address this question, we applied 0.1 to 6% DMSO for 24 h to cochlear organotypic cultures from postnatal day 3 rats and examined its cytotoxic effects. DMSO concentrations of 0.1% and 0.25% caused little or no damage. However, concentrations between 0.5 and 6% resulted in stereocilia damage, hair cell swelling and a dose-dependent loss of hair cells. Hair cell damage began in the basal turn of the cochlea and spread towards the apex with increasing concentration. Surprisingly, DMSO-induced damage was greater for inner hair cells than outer hair cell whereas nearby supporting cells were largely unaffected. Most hair cell death was associated with nuclear shrinkage and fragmentation, morphological features consistent with apoptosis. DMSO treatment induced TUNEL positive staining in many hair cells and activated both initiator caspase-9 and caspase-8 and executioner caspase-3; this suggests that apoptosis is initiated by both intrinsic mitochondrial and extrinsic membrane cell death signaling pathways.

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“…Noise exposure increased levels of 8-isoprostane in the organ of Corti (Ohinata et al, 2000), hydroxyl radicals in cochlear fluids (Ohlemiller et al, 1999) and superoxide anion radicals in the stria vascularis (Yamane et al, 1995;Yamasoba et al, 1998). Reactive oxygen species (ROS) and lipid peroxidation play an important role in noise-and ototoxic-induced hearing loss (Henderson et al, 2006;So et , 2005). Increased levels of reactive oxygen species (ROS) can also trigger the cochlear cell death signaling pathways (Lee et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

A novel dual inhibitor of calpains and lipid peroxidation (BN82270) rescues the cochlea from sound trauma

et al. 2007

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Free radical and calcium buffering mechanisms are implicated in cochlear cell damage that has been induced by sound trauma. Thus in this study we evalua ted the therapeutic effect of a novel dual inhibitor of calpains and of lipid peroxidation (BN 82270) on the permanent hearing and hair cell loss induced by sound trauma.Perfusion of BN 82270 into the scala tympani of the guinea pig cochlea prevented the formation of calpain-cleaved fodrin, translocation of cytochrome c, DNA fragmentation and hair cell degeneration caused by sound trauma. This was confirmed by functional tests in vivo, showing a clear dose-dependent reduction of permanent hearing loss (ED 50 = 4.07 µM) with almost complete protection at 100 µM.Furthermore, BN82270 still remained effective even when applied onto the round window membrane after sound trauma had occurred, within a therapeutic window of 24hours. This indicates that BN 82270 may be of potential therapeutic value in treating the cochlea after sound trauma.

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

Cited by 66 publications

References 51 publications

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Cytotoxic effects of dimethyl sulphoxide (DMSO) on cochlear organotypic cultures

A novel dual inhibitor of calpains and lipid peroxidation (BN82270) rescues the cochlea from sound trauma

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