Pivotal Role of Harakiri in the Induction and Prevention of Gentamicin-Induced Hearing Loss

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 micro...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 44; pp. 16019 - 16024
Main Authors Gilda M. Kalinec, Fernandez-Zapico, Martin E., Urrutia, Raul, Nora Esteban-Cruciani, Shanping Chen, Kalinec, Federico, Reese, Thomas S.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 01.11.2005
National Acad Sciences
Subjects
Animals
Animals, Newborn
Apoptosis
Apoptosis - drug effects
Apoptosis Regulatory Proteins
Biological Sciences
Carnitine - pharmacology
Carnitine - therapeutic use
Cell Line
Cell lines
Cochlea
Cochlea - pathology
Deafness
Female
Gentamicins - adverse effects
Guinea Pigs
Hair cells
Hearing loss
Hearing Loss - chemically induced
Hearing Loss - etiology
Hearing Loss - prevention & control
Medical research
Mitogen-Activated Protein Kinase 3 - metabolism
Neurons
Neuropeptides - genetics
Neuropeptides - physiology
Newborns
Outer hair cells
Pregnancy
Proteins
Ribonucleic acid
RNA
Rodents
Signal transduction
Small interfering RNA
Toxicity
Up regulation
Up-Regulation - drug effects
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Summary: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 upregulation 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.
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Conflict of interest statement: No conflicts declared.
G.M.K. and M.E.F.-Z. contributed equally to this work.
Abbreviations: LCAR, l-carnitine; Hrk, Harakiri; ABR, auditory brainstem response; SEM, scanning electron microscopy; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; siRNA, small interfering RNA; OHC, outer hair cell; MAPK, mitogen-activated protein kinase; p, phosphorylated; I, inhibitor.
Communicated by Thomas S. Reese, National Institutes of Health, Bethesda, MD, September 14, 2005
Author contributions: G.M.K., M.E.F.-Z., S.C., and F.K. performed research; G.M.K., M.E.F.-Z., R.U., and F.K. analyzed data; R.U. contributed new reagents/analytic tools; N.E.-C. and F.K. designed research; and R.U. and F.K. wrote the paper.
To whom correspondence should be addressed at: Department of Cell and Molecular Biology, House Ear Institute, 2100 West Third Street, Los Angeles, CA 90057. E-mail: fkalinec@hei.org.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0508053102