A protein derived from the fusion of TAT peptide and FNK, a Bcl-xL derivative, prevents cochlear hair cell death from aminoglycoside ototoxicity in vivo
✍ Scribed by Akinori Kashio; Takashi Sakamoto; Keigo Suzukawa; Sadamitsu Asoh; Shigeo Ohta; Tatsuya Yamasoba
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 289 KB
- Volume
- 85
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
Abstract
We constructed a powerful artificial cytoprotective protein, FNK, from an antiapoptotic member of the BCL‐2 family, Bcl‐x~L~. To test the efficacy of FNK in protecting cochlear hair cells (HCs) from aminoglycoside‐induced cell death in vivo, we fused FNK with protein transduction domain, TAT, of the HIV/Tat protein to construct a fusion protein of TAT‐FNK. We demonstrated that, after an intraperitoneal administration to guinea pigs, TAT‐myc‐FNK protein was diffusely distributed in the cochlea, most prominently in the HCs and supporting cells, followed by the spiral ganglion cells, 3 hr after the injection. We next demonstrated that TAT‐FNK attenuated cochlear damage induced by an ototoxic combination of kanamycin sulfate (KM) and ethacrynic acid (EA) administered at 2 different dosages: 400 mg/kg KM + 50 mg/kg EA and 200 mg/kg KM + 40 mg/kg EA. TAT‐FNK or vehicle was intraperitoneally injected from 3 hr before through 5 hr after inducing the ototoxic insults, 14 days after which auditory brainstem response (ABR) and HC loss were evaluated. In comparison with vehicle‐administered controls, the TAT‐FNK protein significantly attenuated ototoxic drug‐induced ABR threshold shifts and the extent of HC death at either dosage. The TAT‐FNK protein also significantly reduced the amount of cleaved poly‐(ADP‐ribose) polymerase‐positive HCs 8 hr after the ototoxic insults compared with that in the vehicle‐administered controls. These findings indicate that systemically administered TAT‐FNK was successfully delivered to the guinea pig cochlea and effectively prevented apoptotic cell death of the cochlear HCs induced by KM and EA. © 2007 Wiley‐Liss, Inc.