Abstract
The cell-penetrating peptide GV1001 has been investigated as an anticancer agent and recently demonstrated anti-oxidant and anti-inflammatory effects. It has shown a protective effect on a kanamycin (KM)-induced ototoxicity mouse model. In the present study, we administered GV1001 at different time points after inducing hair cell damage, and examined if it rescues hair cell loss and restores hearing. A deaf mouse model was created by intraperitoneal injection of KM and furosemide. First, to test the early temporal change of hearing and extent of hair cell damage after KM and furosemide injection, hearing and outer hair cells (OHCs) morphology were evaluated on day 1, day 2 and day 3 after injection. In the second experiment, following KM and furosemide injection, GV1001, dexamethasone, or saline were given for three consecutive days at different time points: D0 group (days 0, 1, and 2), D1 group (days 1, 2, and 3), D3 group (days 3, 4, and 5) and D7 group (days 7, 8, and 9). The hearing thresholds were measured at 8, 16, and 32 kHz before ototoxic insult, and 7 days and 14 days after KM and furosemide injection. After 14 days, each turn of the cochlea was imaged to evaluate OHCs damage. GV1001-treated mice showed significantly less hearing loss and OHCs damage than the saline control group in the D0, D1 and D3 groups (p < 0.0167). However, there was no hearing restoration or intact hair cell in the D7 group. GV1001 protected against cochlear hair cell damage, and furthermore, delayed administration of GV1001 up to 3 days rescued hair cell damage and hearing loss in KM/furosemide-induced deaf mouse model.
Highlights
Aminoglycoside antibiotics are used in the treatment of gram-negative bacterial infections, multi-drug resistant tuberculosis, and other hospital acquired serious infections
Aminoglycoside induced hair cells impairment by first inducing disarray of stereocilia and inflammatory changes in inner ear structures (Nakagawa et al, 1998; Cunningham et al, 2002; Kitahara et al, 2005; Tabuchi et al, 2007), terminating in apoptotic cell death through the formation of reactive oxygen species (ROS) including free radicals (Forge and Fradis, 1985; Priuska and Schacht, 1995)
In Experiment 1, to assess the initial temporal change of hearing and the extent of hair cell damage in this deaf mouse model, total nine mice were divided into three groups: Day-1 (N = 3), Day-2 (N = 3) and Day-3 (N = 3)
Summary
Aminoglycoside antibiotics are used in the treatment of gram-negative bacterial infections, multi-drug resistant tuberculosis, and other hospital acquired serious infections. Aminoglycosides result in hair cell death by either caspase-dependent or -independent mechanisms (Rybak and Ramkumar, 2007). Aminoglycoside induced hair cells impairment by first inducing disarray of stereocilia and inflammatory changes in inner ear structures (Nakagawa et al, 1998; Cunningham et al, 2002; Kitahara et al, 2005; Tabuchi et al, 2007), terminating in apoptotic cell death through the formation of reactive oxygen species (ROS) including free radicals (Forge and Fradis, 1985; Priuska and Schacht, 1995). A novel peptide vaccine GV1001, which is a cell-penetrating peptide (16-amino-acid sequence) derived from the active site of human telomerase reverse transcriptase (hTERT), has been investigated as an anticancer agent. GV1001 binds multiple human leukocyte antigen (HLA) class II molecules and elicits combined CD4 and CD8 T-cell responses (Kyte et al, 2011)
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