Common forms of preventable hearing loss are drug and noise-induced hearing loss which are
believed to be produced by a similar mechanism. The generation of reactive oxygen species
appears to be a common mechanism mediating hearing loss produced by these different sources. As
such a number of laboratories have focused their research towards identifying the sources of
ROS production in the cochlea following administration of chemotherapeutic agents or noise
exposure. This led to the identification of ROS generating enzymes such as xanthine oxidases
nitric oxide synthase and NADPH oxidases which are activated and or induced during the
development of hearing loss. A consequence of these findings was the implementation of
antioxidants in preclinical studies for the treatment of hearing loss. These antioxidants have
provided different levels of protection in animal and human studies but none of these have
been approved by the US Food and Drug Administration for the treatment of hearing loss.More
recently it was shown that noise-induced hearing loss was associated with recruitment of
inflammatory cells and mediators in the cochlea. This finding would suggest that noise could
produce injury to the cochlea which stimulates local and or circulating inflammatory cells. A
similar finding was observed in the cochlea following administration of the anticancer drug
cisplatin. In addition our laboratory and others have provided a plausible mechanism by which
noise or chemotherapeutic agents could stimulate the inflammatory response. Surprisingly this
mechanism involves ROS activation of transcription factors linked to inflammatory processes in
the cochlea. These studies have led to the use of anti-inflammatory agents for the treatment of
hearing loss. Preliminary studies targeting inflammatory cytokines appear especially promising
in preclinical studies. A primary goal of this project is to describe our current understanding
of the oxidant hypothesis of noise and drug-induced hearing loss and show how this relates to
cochlear inflammation. Several different aspects of the cochlear inflammatory process will be
discussed in detail ranging from the sources of inflammatory cells chemokines inflammatory
cytokines and cochlea resident immune cells. Molecular pathways leading to activation of the
local inflammatory process will be highlighted and treatment options will be discussed. The
relevance of certain clinically used anti-inflammatory interventions such as trans-typmanic
steroids will also be discussed. Furthermore we will examine recent patents focusing on the
use of anti-inflammatory agents for the treatment of drug and noise-induced hearing loss.
