Editors' ChoiceANTIBIOTICS

Preventing Hearing Loss

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Science's STKE  08 Nov 2005:
Vol. 2005, Issue 309, pp. tw394
DOI: 10.1126/stke.3092005tw394

Gentamicin is an antibiotic used to treat gram-negative bacterial infections; however, one serious side effect can be irreversible hearing loss due to damage to ear tissues. Kalinec et al. show that exposure to gentamicin in utero increased mortality and caused cochlear damage and hearing loss in newborn guinea pigs. Gentamicin also caused apoptosis of an auditory cell line, HEI-OCI, and this cell death was due to increased expression and abundance of Harakiri (Hrk), a proapoptotic Bcl-2 family member. RNA interference (RNAi) for Hrk blocked gentamicin-induced activation of caspase-3, a measure of apoptosis. Pharmacological inhibition of extracellular signal-regulated kinase 1 and 2 (ERK1/2) also inhibited gentamicin-induced caspase-3 activation, whereas inhibition of c-Jun N-terminal kinase (JNK) increased gentamicin-induced caspase-3 activation. L-carnitine (LCAR), a micronutrient that is known for its neuroprotective effects, inhibited gentamicin-induced hearing loss and cochlear damage when given to pregnant guinea pigs and decreased newborn mortality. LCAR inhibited gentamicin-induced apoptosis and caspase-3 activation in cultured auditory cells. The mechanism by which LCAR acted appeared to be through activation of the JNK pathway, because pharmacological inhibition of JNK blocked the protective effects of LCAR. In cultured cells, LCAR prevented the transcriptional up-regulation of Hrk by gentamicin. Thus, LCAR, which did not block the antibiotic effects of gentamicin, may be a safe supplement that can be used to prevent the ear damage by gentamicin.

G. M. Kalinec, M. E. Fernandez-Zapico, R. Urrutia, N. Esteban-Cruciani, S. Chen, F. Kalinec, Pivotal role of Harakiri in the induction and prevention of gentamicin-induced hearing loss. Proc. Natl. Acad. Sci. U.S.A. 102, 16019-16024 (2005). [Abstract] [Full Text]