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PNAS 102 (44): 16019-16024

Copyright © 2005 by the National Academy of Sciences.


MEDICAL SCIENCES

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

Gilda M. Kalinec * {dagger}, Martin E. Fernandez-Zapico {dagger}, {ddagger}, Raul Urrutia {ddagger}, Nora Esteban-Cruciani §, Shanping Chen *, and Federico Kalinec *, ¶, ||

*Gonda Department of Cell and Molecular Biology, House Ear Institute, Los Angeles, CA 90057; {ddagger}Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, MN 55905; §Children's Hospital at Montefiore and Albert Einstein College of Medicine, Bronx, NY 10461; and Departments of Otolaryngology and Cell and Neurobiology, University of Southern California, Los Angeles, CA 90089

Communicated by Thomas S. Reese, National Institutes of Health, Bethesda, MD, September 14, 2005

Received for publication January 5, 2005.

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.

Key Words: apoptosis • ototoxicity • L-carnitine • extracellular signal-regulated kinase 1/2 • HEI-OC1 cells


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.

Conflict of interest statement: No conflicts declared.

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.

{dagger} G.M.K. and M.E.F.-Z. contributed equally to this work.

|| 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{at}hei.org.

© 2005 by The National Academy of Sciences of the USA


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