Attenuation of cochlear damage from noise trauma by an iron chelator, a free radical scavenger and glial cell line-derived neurotrophic factor in vivo

Tissue injury by reactive oxygen species (ROS) may play a role in noise-induced hearing loss (NIHL). Since iron is involved in ROS generation, we studied if an iron chelator, deferoxamine mesylate (DFO), alone or in combination with mannitol, a hydroxyl scavenger and weak iron chelator, attenuates NIHL. Further, we investigated if glial cell line-derived neurotrophic factor (GDNF) provides additive or synergistic protection of the cochlea from acoustic trauma when given together with DFO and mannitol. Pigmented female guinea pigs were exposed to noise (4 kHz octave band, 115 dB SPL, 5 h). One hour before, immediately after, and 5 h after noise exposure, subjects received an injection of 5 ml saline/kg (control, group I), 100 mg DFO/kg (group II), 15 mg mannitol/kg (group III), or both DFO and mannitol (group IV and V). Animals in group V underwent implantation of an osmotic pump filled with GDNF (100 ng/ml) in the left ear 4 days before noise. Each treatment afforded some protection from noise damage. Group I showed significantly greater outer hair cell loss and threshold shifts at two or more frequencies compared to groups II through V. GDNF provided an additive functional, but not morphological, protection with DFO and mannitol. These findings indicate that iron chelators can attenuate NIHL, as do ROS scavengers, supporting the notion that ROS generation plays a role in NIHL. Additional functional protection provided with GDNF suggests that GDNF may attenuate noise-induced cochlear damage through a mechanism that is additive with antioxidants.