Pivotal role of Harakiri in the induction and prevention of gentamicin-induced hearing loss

Gilda M. Kalinec, Martin E Fernandez-Zapico, Raul Urrutia, Nora Esteban-Cruciani, Shanping Chen, Federico Kalinec

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Gentamicin is a widely used ototoxic agent. In this study, we shed light on the mechanisms underlying gentamicin-induced hearing loss. More importantly, we demonstrate in vivo and in vitro the effectiveness of a strategy for preventing drug-induced hearing loss using L-carnitine (LCAR), a safe micronutrient that plays a key role in energy metabolism and detoxification [Rebouche, C. J. & Seim, H. (1998) Annu. Rev. Nutr. 18, 39-61]. We show that LCAR prevents changes in hearing threshold and cochlear damage in newborn guinea pigs exposed to gentamicin in utero. Mechanistically, gentamicin-induced apoptosis of auditory cells is mediated by the extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase (MAPK) pathway through up-regulation of the proapoptotic factor Harakiri (Hrk). Most important, small interfering RNA (siRNA) experiments demonstrate that Hrk up-regulation is crucial for gentamicin-induced apoptosis. LCAR, in contrast, prevents both gentamicin-induced Hrk up-regulation and apoptosis acting by means of c-Jun N-terminal kinase (JNK). Together, these results outline pathways for gentamicin-induced hearing loss and its prevention and assign a key role to Hrk in these processes. Thus, our data offer a conceptual framework for designing clinical trials using a safe micronutrient, LCAR, as a simple preventive strategy for iatrogenically induced ototoxicity.

Original languageEnglish (US)
Pages (from-to)16019-16024
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number44
DOIs
StatePublished - Nov 1 2005

Fingerprint

Gentamicins
Hearing Loss
Carnitine
Up-Regulation
Micronutrients
Apoptosis
Mitogen-Activated Protein Kinase 3
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 1
Cochlea
Mitogen-Activated Protein Kinases
Energy Metabolism
Small Interfering RNA
Hearing
Guinea Pigs
Clinical Trials
Pharmaceutical Preparations

Keywords

  • Apoptosis
  • Extracellular signal-regulated kinase 1/2
  • HEI-OC1 cells
  • L-carnitine
  • Ototoxicity

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Pivotal role of Harakiri in the induction and prevention of gentamicin-induced hearing loss. / Kalinec, Gilda M.; Fernandez-Zapico, Martin E; Urrutia, Raul; Esteban-Cruciani, Nora; Chen, Shanping; Kalinec, Federico.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 44, 01.11.2005, p. 16019-16024.

Research output: Contribution to journalArticle

Kalinec, Gilda M. ; Fernandez-Zapico, Martin E ; Urrutia, Raul ; Esteban-Cruciani, Nora ; Chen, Shanping ; Kalinec, Federico. / Pivotal role of Harakiri in the induction and prevention of gentamicin-induced hearing loss. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 44. pp. 16019-16024.
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