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 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.
Kalinec
Gilda M
GM
Gonda Department of Cell and Molecular Biology, House Ear Institute, Los Angeles, CA 90057, USA. fkalinec@hei.org
Fernandez-Zapico
Martin E
ME
Urrutia
Raul
R
Esteban-Cruciani
Nora
N
Chen
Shanping
S
Kalinec
Federico
F
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D002331:Carnitine / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D003051:Cochlea / Q000473:pathology; D005260:Female; D005839:Gentamicins / Q000009:adverse effects*; D006168:Guinea Pigs; D034381:Hearing Loss / Q000139:chemically induced* / Q000209:etiology / Q000517:prevention & control*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D015854:Up-Regulation / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; D005839:Gentamicins; C484586:HRK protein, human; D009479:Neuropeptides; D048052:Mitogen-Activated Protein Kinase 3; D002331:Carnitine