The role of PKCzeta in amikacin-induced apoptosis in the cochlea: prevention by aspirin.
Aminoglycoside antibiotics are ototoxic, inducing irreversible sensorineural hearing loss mediated by oxidative and excitotoxic stresses. The NF-kappaB pathway is involved in the response to aminoglycoside damage in the cochlea. However, the molecular mechanisms of this ototoxicity remain unclear. We investigated the expression of PKCzeta, a key regulator of NF-kappaB activation, in response to aminoglycoside treatment. Amikacin induced PKCzeta cleavage and nuclear translocation. These events were concomitant with chromatin condensation and paralleled the decrease in NF-kappaB (p65) levels in the nucleus. Amikacin also induced the nuclear translocation of apoptotic inducing factor (AIF). Prior treatment with aspirin prevented PKCzeta cleavage and nuclear translocation. Thus, aspirin counteracts the early effects of amikacin, thereby protecting hair cells and spiral ganglion neurons. These results demonstrate that PKCzeta acts as sentinel connecting specific survival pathways to mediate cellular responses to amikacin ototoxicity.
Lecain
Eric
E
Hôpital Lariboisière, Service ORL, 2 rue Ambroise Paré, 75010, Paris, France.
Omri
Boubaker
B
Behar-Cohen
Francine
F
Tran Ba Huy
Patrice
P
Crisanti
Patricia
P
D000583:Amikacin / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology*; D001300:Audiometry, Evoked Response; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003051:Cochlea / Q000166:cytology* / Q000201:enzymology*; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D013136:Spiral Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D051996:Transcription Factor RelA / Q000378:metabolism; D000099221:Protein Kinase C zeta
D000583:Amikacin; D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051033:Apoptosis Inducing Factor; D001241:Aspirin; D011493:Protein Kinase C; D051996:Transcription Factor RelA; D000099221:Protein Kinase C zeta