title: Topical application of the antiapoptotic TAT-FNK protein prevents aminoglycoside-induced ototoxicity.
abstract: We previously demonstrated that an artificial protein, TAT-FNK, has antiapoptotic effects against cochlear hair cell (HC) damage caused by ototoxic agents when applied systemically. To examine the feasibility of topical protein therapy for inner ear disorders, we investigated whether gelatin sponge soaked with TAT-FNK and placed on the guinea pig round window membrane (RWM) could deliver the protein to the cochlea and attenuate aminoglycoside (AG)-induced cochlear damage in vivo. First, we found that the immunoreactivity of TAT-myc-FNK was distributed throughout the cochlea. The immunoreactivity was observed from 1-24 h after application. When Tat-FNK was applied 1 h before ototoxic insult (a combination of kanamycin sulfate and ethacrynic acid), auditory brainstem response threshold shifts and the extent of HC death were significantly attenuated. When cochlear organotypic cultures prepared from P5 rats were treated with kanamycin, TAT-FNK significantly reduced the extent of caspase-9 activation and HC death. These findings indicate that TAT-FNK topically applied on the RWM can enter the cochlea by diffusion and effectively prevent AG-induced apoptosis of cochlear HCs by suppressing the mitochondrial caspase-9 pathway.
authors.affiliation: Faculty of Medicine, Department of Otolaryngology and Head and Neck Surgery, The University of Tokyo, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kashio
authors.forename: T
authors.initials: T
authors.lastname: Sakamoto
authors.forename: A
authors.initials: A
authors.lastname: Kakigi
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Suzukawa
authors.forename: K
authors.initials: K
authors.lastname: Kondo
authors.forename: Y
authors.initials: Y
authors.lastname: Sato
authors.forename: S
authors.initials: S
authors.lastname: Asoh
authors.forename: S
authors.initials: S
authors.lastname: Ohta
authors.forename: T
authors.initials: T
authors.lastname: Yamasoba
mesh_terms: D000287:Administration, Topical; D000617:Aminoglycosides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053453:Caspase 9 / Q000378:metabolism; D003051:Cochlea / Q000187:drug effects* / Q000378:metabolism; D004976:Ethacrynic Acid / Q000494:pharmacology / Q000633:toxicity; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D015696:Gene Products, tat / Q000008:administration & dosage / Q000494:pharmacology*; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000187:drug effects; D007612:Kanamycin / Q000494:pharmacology; D007759:Labyrinth Diseases / Q000139:chemically induced / Q000517:prevention & control*; D018696:Neuroprotective Agents; D017346:Protein Serine-Threonine Kinases / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D012405:Round Window, Ear; D025521:Tumor Suppressor Proteins; D000097868:Polo-like Kinases
chemical_list: D000617:Aminoglycosides; D053453:Caspase 9; D004976:Ethacrynic Acid; D015696:Gene Products, tat; D007612:Kanamycin; D018696:Neuroprotective Agents; D017346:Protein Serine-Threonine Kinases; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; C581243:TAT-FNK fusion protein; C486256:PLK3 protein, human; D000097868:Polo-like Kinases