Dexamethasone protects organ of corti explants against tumor necrosis factor-alpha-induced loss of auditory hair cells and alters the expression levels of apoptosis-related genes

C. T. Dinh, S. Haake, S. Chen, K. Hoang, E. Nong, A. A. Eshraghi, T. J. Balkany, T. R. Van De Water

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Objective: Determine the molecular mechanism(s) behind tumor necrosis factor-alpha (TNFα)-induced loss of auditory hair cells and the ability of dexamethasone base (DXMb) to protect against TNFα ototoxicity. Methods: Hair cell counts: Three-day-old rat organ of Corti explants were cultured under three different conditions: 1) untreated-control; 2) TNFα (2 μg/ml); and 3) TNFα (2 μg/ml)+DXMb (70 μg/ml) for 4 days, fixed, and stained with FITC-phalloidin. Hair cells were counted in the basal and middle turns. Gene expression: total RNA was extracted from the three different groups of explants at 0, 12, 24 and 48 h. Using quantitative real-time RT-PCR, mRNAs were transcribed into cDNAs and amplification was performed using primers for rat ß-actin (housekeeping gene), TNFR1, Bcl-2, Bax, and Bcl-xl. Results: DXMb protected explant hair cells from TNFα-induced loss. Bax gene expression was greater in TNFα-exposed explants compared with TNFα+DXMb-treated explants at 48 h (P=0.023), confirmed by the increase in the Bax/Bcl-2 ratio at 48 h (P<0.001). These results correlated with increased TNFR1 expression at 24 h (P=0.038). DXMb otoprotection in TNFα-exposed cultures was accompanied by an up-regulation of Bcl-xl at both the 24 (P<0.001) and 48 h time points (P=0.030) and up-regulation of Bcl-2 expression at 24 h (P=0.018). DXMb treatment also prevented increases in the expression levels of Bax, TNFR1, and the Bax/Bcl-2 ratio that occurred in untreated TNFα-exposed explants. Conclusions: TNFα's ototoxicity may be mediated through an up-regulation of Bax and TNFR1 expression as well as an increase in the Bax/Bcl-2 ratio. DXMb protects the organ of Corti against TNFα ototoxicity by up-regulating Bcl-2 and Bcl-xl expression and by inhibiting TNFα-induced increases in Bax, TNFR1, and the Bax/Bcl-2 ratio. These results support the use of local dexamethasone treatment to conserve hearing following a trauma.

Original languageEnglish (US)
Pages (from-to)405-413
Number of pages9
JournalNeuroscience
Volume157
Issue number2
DOIs
StatePublished - Nov 19 2008

Keywords

  • cell survival
  • cochlea
  • corticosteroids
  • nuclear factor kappa B
  • pro-inflammatory cytokine
  • trauma-induced hair cell loss

ASJC Scopus subject areas

  • Neuroscience(all)

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